Oxazolidinone compounds and methods of use thereof as antibacterial agents

ABSTRACT

The present invention discloses oxazolidinone compounds of Formula (I): (I) and pharmaceutically acceptable salts thereof, wherein A and E, are as defined herein. The present invention also relates to compositions which comprise at least one oxazolidinone compound of the invention. The invention also provides methods for inhibiting growth of mycobacterial cells as well as a method of treating mycobacterial infections by Mycobacterium tuberculosis comprising administering a therapeutically effective amount of an oxazolidinone of the invention and/or a pharmaceutically acceptable salt thereof, or a composition comprising such compound and/or salt.

FIELD OF THE INVENTION

The present invention relates to novel oxazolidinone compounds usefulfor the treatment of bacterial infections, particularly mycobacterialinfections. The invention also relates to methods of use ofoxazolidinone compounds for the treatment of mycobacterial infectionssuch as those caused by Mycobacteria tuberculosis.

BACKGROUND OF THE INVENTION

Mycobacterium is a genus of bacterium, neither truly gram-positive nortruly gram-negative, including pathogens responsible for tuberculosis(M. tuberculosis) and leprosy (M. leprae). Tuberculosis (TB), inparticular, despite the availability of anti-TB drugs such as isoniazideand rifampin, is considered to be one of the worlds deadliest diseases.According to World Health Organization, in 2012, there were 8.6 millionnew TB cases and 1.3 million TB deaths. See, Global tuberculosis report2013 published by the World Health Organization. Complicating the TBepidemic is the rising tide of multi-drug-resistant strains, and thedeadly association with HIV. People who are HIV-positive and infectedwith TB are 30 times more likely to develop active TB than people whoare HIV-negative, and TB is responsible for the death of one out ofevery three people with HIV/AIDS worldwide. See, e.g., Kaufmann et al.,Trends Microbiol. 1: 2-5 (1993) and Bloom et al., N. Engl. J. Med. 338:677-678 (1998).

Mycobacteria other than M. tuberculosis are increasingly found inopportunistic infections that plague the AIDS patient. Organisms fromthe M. avium-intracellulare complex (MAC), especially serotypes four andeight, account for 68% of the mycobacterial isolates from AIDS patients.Enormous numbers of MAC are found (up to 1010 acid-fast bacilli per gramof tissue), and consequently, the prognosis for the infected AIDSpatient is poor.

Oxazolidinones are a class of compounds containing 2-oxazolidone, a5-membered ring containing nitrogen and oxygen, which are used asantimicrobials. See, e.g. WO 2009157423. In general, oxazolidinones areknown to be monoamine oxidase inhibitors and to have activity againstgram-positive microrganisms. WO 2006022794, Suzuki et al., Med. Chem.Lett. 4:1074-1078 (2013), Yang et al., J. Med. Chem. 58:6389-6409(2015), Shaw et al., Ann. N.Y. Acad. Sci. 1241:48-70 (2011), Severaloxazolidinone antibiotics have been approved or are in clinical trialsfor the treatment of gram-positive bacterial infections such asmethicillin resistant Staphylococcus aureus. Examples of oxazolidinoneantibiotics include linezolid (Zyvox™, Pfizer Inc., New York, N.Y.) andtedizolid (Sivextro™, Merck Sharp & Dohme Corp., Kenilworth, N.J.).Tedizolid is used to treat acute bacterial skin and skin structureinfections caused by specific susceptible gram-positive bacteria.Linezolid is indicated for the treatment of several infections caused bysusceptible strains of gram-positive microorganisms including nosocomialpneumonia, complicated skin and skin structure infections, andcommunity-acquired pneumonia. In addition, it is currently being testedfor the treatment of multi-drug resistant (MDR) and extensivelydrug-resistant (XDR) Mycobacterium tuberculosis (Mtb) in clinicaltrials. Lee et al., N. Engl. J. Med 367: 1508-18 (2012). Despiteclinical efficacy in treating these diseases, long-term use of linezolidhas been associated with adverse events including myelosuppression(including anemia and leukopenia) (Hickey et al., Therapy 3(4):521-526(2006), neuropathy, and serotonin syndrome. These adverse events arehypothesized to be associated with the inhibition of mitochondrialprotein synthesis. Flanagan et al., Antimicrobial Agents andChemotherapy 59(1):178-185 (2015).

Development of oxazolidinone antibiotics that are safer than approvedoxazolidinones yet at least as effective would greatly benefit Mtbpatients.

SUMMARY OF THE INVENTION

The present invention is directed to certain novel oxazolidinonecompounds which have antibacterial activity. The compounds, and theirpharmaceutically acceptable salts, can be useful, for example, for thetreatment of bacterial infections, for example, mycobacterialinfections.

The present invention is direct to compounds of Formula I, orpharmaceutically acceptable salts thereof:

or a pharmaceutically acceptable salt thereof,wherein:

E is a 6-membered aryl or a 5- or 6-membered heteroaryl containing fromone to three heteroatoms independently selected from S, O, and N,wherein said aryl and said heteroaryl are optionally substituted with upto four substituents, which are independently selected from halogen,—CN, —CF₃, —CHF₂, —CH₂NH₂, —CH₂NHCOCH₃, —OCF₃, —OCHF₂, —OH,—O—(C₁-C₆)alkyl, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl;

A is a heterocycle optionally substituted with up to four R⁸, or an aryloptionally substituted with up to four R⁸;

each occurrence of R⁸ is independently selected from H, halogen, C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, —OC₁-C₆ alkyl, benzyl,—OCF₃, —OCHF₂, —OR³, ═O, —CN, —NO₂, —SR³, —SF₅, —SCF₃, —SOR³, —SO₂R³,—S(═O)(═N)R², —N(R²)₂, —NR²COR³, —SO₂N(R²)₂, —NR²SO₂R³, —COOH, —COR⁹,—COOR³, —CON(R²)₂, —CO(R²)₂ and —C(R⁹)₂N(R²)₂, wherein said C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, —OC₁-C₆ alkyl, and benzyl areoptionally substituted with up to four F, —OCH₃, —OH, ═O, NH₂, NHCH₃,SO₂R³, and N(CH₃)₂;

each occurrence of R² is independently selected from H, C₁-C₆ alkyl,C₂-C₆ alkenyl, and C₃-C₆ cycloalkyl, wherein said C₁-C₆ alkyl, saidC₂-C₆ alkenyl, and said C₃-C₆ cycloalkyl can be optionally substitutedwith up to four substituents, which are independently selected fromhalogen, —OCH₃, —OH, —NH₂, —NHCH₃, and —N(CH₃)₂;

R³ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆ heterocycloalkyl and C₃-C₆cycloalkyl, wherein said C₁-C₆ alkyl, said C₂-C₆ alkenyl, said C₃-C₆heterocycloalkyl and said C₃-C₆ cycloalkyl can be optionally substitutedwith up to four substituents, which are independently selected fromhalogen, methyl, —OCH₃, —OH, —NH₂, —NHCH₃, and —N(CH₃)₂; and eachoccurrence of R⁹ is independently selected from H, C₁-C₆ alkyl, andC₃-C₆ cycloalkyl.

More particularly, the present invention includes compounds of FormulaI, or pharmaceutically acceptable salts thereof:

wherein:

E is a 6-membered aryl or a 5- or 6-membered heteroaryl containing fromone to three heteroatoms independently selected from S, O, and N,wherein said aryl and said heteroaryl are optionally substituted with upto four substituents, which are independently selected from halogen,—CN, —CF₃, —CHF₂, —CH₂NH₂, —CH₂NHCOCH₃, —OCF₃, —OCHF₂, —OH,—O—(C₁-C₆)alkyl, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl;

A is a heterocycle substituted or optionally substituted with up to fourR⁸, or an aryl substituted with up to four R⁸;

each occurrence of R⁸ is independently selected from H, halogen, C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, benzyl, —OCF₃, —OCHF₂,—OR³, ═O, —CN, —NO₂, —SR³, —SF₅, —SCF₃, —SOR³, —SO₂R³, —S(═O)(═N)R²,—N(R²)₂, —NR²COR³, —SO₂N(R²)₂, —NR²SO₂R³, —COOH, —COR⁹, —COOR³,—CON(R²)₂, —CO(R²)₂ and —C(R⁹)₂N(R²)₂, wherein said C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₃-C₆ heterocycloalkyl, and benzyl are optionallysubstituted with up to four F, —OCH₃, —OH, ═O, NH₂, NHCH₃, and N(CH₃)₂;and

each occurrence of R² is independently selected from H, C₁-C₆ alkyl,C₂-C₆ alkenyl, and C₃-C₆ cycloalkyl, wherein said C₁-C₆ alkyl, saidC₂-C₆ alkenyl, and said C₃-C₆ cycloalkyl can be optionally substitutedwith up to four substituents, which are independently selected fromhalogen, —OCH₃, —OH, NH₂, NHCH₃, and N(CH₃)₂;

R³ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₃-C₆ cycloalkyl, wherein saidC₁-C₆ alkyl, said C₂-C₆ alkenyl and said C₃-C₆ cycloalkyl can beoptionally substituted with up to four substituents, which areindependently selected from halogen, —OCH₃, —OH, NH₂, NHCH₃, andN(CH₃)₂;

each occurrence of R⁹ is independently selected from H, C₁-C₆ alkyl,N(R²)₂ and C₃-C₆ cycloalkyl.

Also described herein are prodrugs of the compounds of Formula I,represented by the formula of Formula II:

wherein:

E is a 6-membered aryl or a 5- or 6-membered heteroaryl containing fromone to three heteroatoms independently selected from S, O, and N,wherein said aryl and said heteroaryl are optionally substituted with upto four substituents, which are independently selected from halogen,—CN, —CF₃, —CHF₂, —CH₂NH₂, —CH₂NHCOCH₃, —OCF₃, —OCHF₂, —OH,—O—(C₁-C₆)alkyl, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl;

A is a heterocycle optionally substituted with up to four R⁸, or an aryloptionally substituted with up to four R⁸;

each occurrence of R⁸ is independently selected from H, halogen, C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, —OC₁-C₆ alkyl, benzyl,—OCF₃, —OCHF₂, —OR³, ═O, —CN, —NO₂, —SR³, —SF₅, —SCF₃, —SOR³, —SO₂R³,—S(═O)(═N)R², —N(R²)₂, —NR²COR³, —SO₂N(R²)₂, —NR²SO₂R³, —COOH, —COR⁹,—COOR³, —CON(R²)₂, —CO(R²)₂ and —C(R⁹)₂N(R²)₂, wherein said C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, —OC₁-C₆ alkyl, and benzyl areoptionally substituted with up to four F, —OCH₃, —OH, ═O, NH₂, NHCH₃,SO₂R³, and N(CH₃)₂;

each occurrence of R² is independently selected from H, C₁-C₆ alkyl,C₂-C₆ alkenyl, and C₃-C₆ cycloalkyl, wherein said C₁-C₆ alkyl, saidC₂-C₆ alkenyl, and said C₃-C₆ cycloalkyl can be optionally substitutedwith up to four substituents, which are independently selected fromhalogen, —OCH₃, —OH, —NH₂, —NHCH₃, and —N(CH₃)₂;

R³ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆ heterocycloalkyl and C₃-C₆cycloalkyl, wherein said C₁-C₆ alkyl, said C₂-C₆ alkenyl, said C₃-C₆heterocycloalkyl and said C₃-C₆ cycloalkyl can be optionally substitutedwith up to four substituents, which are independently selected fromhalogen, methyl, —OCH₃, —OH, —NH₂, —NHCH₃, and —N(CH₃)₂; and

each occurrence of R⁹ is independently selected from H, C₁-C₆ alkyl, andC₃-C₆ cycloalkyl.

The present invention also relates to a pharmaceutical composition fortreating a bacterial infection in a subject, particularly an M.tuberculosis infection, comprising an oxazolidinone compound of theinvention and a pharmaceutically acceptable carrier, diluent orexcipient.

The Compounds of Formula I and pharmaceutically acceptable salts andprodrugs thereof (also referred to herein as the “OxazolidinoneCompounds”) can be useful, for example, for inhibiting the growth ofMycobacterium tuberculosis, and/or for treating or preventingtuberculosis in a patient. Without being bound by any specific theory,it is believed that uses of the Oxazolidinone Compounds of the inventionfor the treatment of tuberculosis are likely to cause lessmyelosuppression than known oxazolidinone compounds such as linezolidbecause they are not associated with a high degree of inhibition ofmitochondrial protein synthesis (see Examples).

The present invention is also directed to 1) methods of treatingtuberculosis in a subject in need of treatment thereof, comprisingadministering to the subject an effective amount of an OxazolidinoneCompound; and 2) uses of an Oxazolidinone Compound for the treatment oftuberculosis.

Embodiments, sub-embodiments and features of the present invention areeither further described herein or will be apparent from the ensuingdescription, examples and appended claims.

DETAILED DESCRIPTION OF THE INVENTION

Oxazolidinones were originally developed for use in treatinggram-positive bacterial infections, particularly, methicillin-resistantS. aureus infections. As shown in the Examples, in vitro testing of theoxazolidinone compounds of Formula I revealed such compounds hadexcellent potency in inhibiting the growth of Mycobacteria tuberculosis.Additionally, Oxazolidinone Compounds of the invention are notassociated with a high degree of mitochondrial protein synthesisinhibition. Thus, compounds of Formula I and their pharmaceuticallyacceptable salts and prodrugs are expected to be useful for thetreatment of mycobacterial tuberculosis (Mtb), yet not lead to the sideeffects such as myelosuppression that are associated with theoxazolidinone linezolid, which is approved for treatment ofGram-positive infections. Therefore, such compounds would havesignificant advantages over linezolid and analogs as Mtb therapeuticagents.

The Compounds of Formula (I)

In one aspect, the present invention includes compounds of Formula I:

and pharmaceutically acceptable salts thereof, wherein A and E aredefined above for the Compounds of Formula (I); wherein the compoundsmay be suitable for use for the treatment of bacterial infections,particularly mycobacterial infections.

A first embodiment of the invention (Embodiment E1) is a compound ofFormula I, or a pharmaceutically acceptable salt thereof, wherein A isan aryl optionally substituted with up to four R⁸; and wherein all othervariables are as originally defined (i.e. as defined in Formula I in theSummary of the Invention.

In a sub-embodiment of Embodiment E1, A is a 6-membered aryl. In stillfurther sub-embodiments, A is a 7-, 8-, 9-, 10-, 11-, 12-, 13-, or14-membered aryl.

A second embodiment (Embodiment E2) is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein, A is a heterocycle orheteroaryl, wherein from 1 to 4 of the ring atoms is independently O, N,or S and the remaining ring atoms are carbon atoms, and all othervariables are as defined in the Summary of the Invention.

In a sub-embodiment of Embodiment E2, A is a 5-membered heteroarylcontaining one heteroatom. In a further sub-embodiment, A is a5-membered heteroaryl containing two heteroatoms. In anothersub-embodiment A is a 5-membered heteroaryl containing threeheteroatoms. In a still further sub-embodiment A is a 5-memberedheteroaryl containing four heteroatoms. In another sub-embodiment, A isa 6-membered heteroaryl containing one heteroatom. In a furthersub-embodiment, A is a 6-membered heteroaryl containing two heteroatoms.In another sub-embodiment A is a 6-membered heteroaryl containing threeheteroatoms. In a still further sub-embodiment A is a 6-memberedheteroaryl containing four heteroatoms. In still furthersub-embodiments, A is a 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-memberedheteroaryl containing from one to four heteroatoms selected from N, O,and S.

In a sub-embodiment of Embodiment E2, A is a 5-membered heterocyclecontaining one heteroatom. In a further sub-embodiment, A is a5-membered heterocycle containing two heteroatoms. In anothersub-embodiment A is a 5-membered heterocycle containing threeheteroatoms. In a still further sub-embodiment A is a 5-memberedheterocycle containing four heteroatoms. In another sub-embodiment, A isa 6-membered heterocycle containing one heteroatom. In a furthersub-embodiment, A is a 6-membered heterocycle containing twoheteroatoms. In another sub-embodiment A is a 6-membered heterocyclecontaining three heteroatoms. In a still further sub-embodiment A is a6-membered heterocycle containing four heteroatoms. In still furthersub-embodiments, A is a 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-memberedheterocycle containing from one to four heteroatoms selected from N, O,and S.

A third embodiment (Embodiment E3) is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein A is a monocyclicsaturated or partially unsaturated ring optionally substituted with upto four R⁸, wherein from 1 to 4 of the ring atoms is independently O, N,or S and the remaining ring atoms are carbon atoms, and all othervariables are as defined in the Summary of the Invention.

In a sub-embodiment of Embodiment E3, A is a 5-membered monocyclicsaturated or partially unsaturated ring containing one heteroatom. In afurther sub-embodiment, A is a 5-membered monocyclic saturated orpartially unsaturated ring containing two heteroatoms. In anothersub-embodiment A is a 5-membered monocyclic saturated or partiallyunsaturated ring containing three heteroatoms. In a still furthersub-embodiment A is a 5-membered monocyclic saturated or partiallyunsaturated ring containing four heteroatoms. In another sub-embodiment,A is a 6-membered monocyclic saturated or partially unsaturated ringcontaining one heteroatom. In a further sub-embodiment, A is a6-membered monocyclic saturated or partially unsaturated ring containingtwo heteroatoms. In another sub-embodiment A is a 6-membered monocyclicsaturated or partially unsaturated ring containing three heteroatoms. Ina still further sub-embodiment A is a 6-membered monocyclic saturated orpartially unsaturated ring containing four heteroatoms.

A fourth embodiment (Embodiment E4) is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein, A is a bicyclicsaturated or partially unsaturated ring system, optionally substitutedwith up to four R⁸, wherein from 1 to 4 of the ring atoms isindependently O, N, or S and the remaining ring atoms are carbon atoms,and all other variables are as defined in the Summary of the Invention.

In a sub-embodiment of Embodiment E4, A is a bicyclic saturated orpartially unsaturated ring system containing one heteroatom. In afurther sub-embodiment, A is a bicyclic saturated or partiallyunsaturated ring system containing two heteroatoms. In anothersub-embodiment A is a bicyclic saturated or partially unsaturated ringsystem containing three heteroatoms. In a still further sub-embodiment Ais a bicyclic saturated or partially unsaturated ring system containingfour heteroatoms.

In Embodiments E1-E4 and sub-embodiments of Embodiments E1-E4, A isoptionally substituted with up to four occurrences of R⁸. Insub-embodiments of Embodiments E1-E4 and preceding sub embodimentsthereof, A is substituted with four occurrences of R⁸, which are asoriginally defined. In another sub-embodiment, A is substituted withthree occurrences of R⁸. In a further sub-embodiment, A is substitutedwith two occurrences of R⁸. In yet a further sub-embodiment, A issubstituted with a single occurrence of R⁸. In alternative embodimentsof Embodiments E1-E4, A is unsubstituted.

A fifth embodiment (Embodiment E5) is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein, A is selected fromthe group consisting of:

wherein R⁸ represents up to four optional substituents, which can be thesame or different; andwherein R⁸ and all other variables are as defined in the Summary of theInvention, or wherein, A is selected from the group consisting of:

wherein R⁸ represents up to four optional substituents, which can be thesame or different; andwherein R⁸ and all other variables are as defined in the Summary of theInvention.

In sub-embodiments of Embodiments E5, A is substituted with fouroccurrences of R⁸. In another sub-embodiment, A is substituted withthree occurrences of R⁸. In a further sub-embodiment, A is substitutedwith two occurrences of R⁸. In yet a further sub-embodiment, A issubstituted with a single occurrence of R⁸. In an alternativesub-embodiment of Embodiment E5, A is unsubstituted.

A sixth embodiment (Embodiment E6) is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein, A is selected fromthe group consisting of:

or wherein, A is selected from the group consisting of:

wherein:

m= is 0, 1, 2, or 3;

each occurrence of R⁸ is independently selected from H, halogen, C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, —OC₁-C₆ alkyl, benzyl,—OCF₃, —OCHF₂, —OR³, ═O, —CN, —NO₂, —SR³, —SF₅, —SCF₃, —SOR³, —SO₂R³,—S(═O)(═N)R², —N(R²)₂, —NR²COR³, —SO₂N(R²)₂, —NR²SO₂R³, —COOH, —COR⁹,—COOR³, —CON(R²)₂, —CO(R²)₂ and —C(R⁹)₂N(R²)₂, wherein said C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, —OC₁-C₆ alkyl, and benzyl areoptionally substituted with up to four F, —OCH₃, —OH, ═O, NH₂, NHCH₃,SO₂R³, and N(CH₃)₂;

R¹⁰ is selected from H, C₁-C₆ alkyl and C₃-C₆ cycloalkyl, wherein saidC₁-C₆ alkyl and said C₃-C₆ cycloalkyl are optionally substituted withfrom one to four substituents, which are independently selected from F,—OCH₃, —OH, NH₂, NHCH₃, and N(CH₃)₂;

R¹¹ is selected from H, C₁-C₆ alkyl and C₃-C₆ cycloalkyl, —COR⁹, —COOR³,—CON(R⁹)₂, and —SO₂R⁹;

each occurrence of R¹² is independently selected from H, halogen, C₁-C₆alkyl, C₃-C₆ cycloalkyl, benzyl, —OCF₃, —OCHF₂, —OR³, —CN, —NO₂, —SR³,—SF₅, —SCF₃, —SOR³, —SO₂R³, —S(═O)(═N)R², —N(R²)₂, —NR²COR³, —SO₂N(R²)₂,—NR²SO₂R³, —COOH, —COR⁹, —COOR³, —CON(R²)₂, and —C(R⁹)₂N(R²)₂, whereinsaid C₁-C₆ alkyl, C₃-C₆ cycloalkyl, and benzyl are optionallysubstituted with up to four F, —OCH₃, —OH, NH₂, NHCH₃, and N(CH₃)₂;

R¹³ is selected from H, halogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, benzyl,—OCF₃, —OCHF₂, —OR³, —CN, —NO₂, —SR³, —SF₅, —SCF₃, —SOR³, —SO₂R³,—S(═O)(═N)R², —N(R²)₂, —NR²COR³, —SO₂N(R²)₂, —NR²SO₂R³, —COOH, —COR⁹,—COOR³, —CON(R²)₂, and —C(R⁹)₂N(R²)₂, wherein said C₁-C₆ alkyl, C₃-C₆cycloalkyl, and benzyl are optionally substituted with up to four F,—OCH₃, —OH, NH₂, NHCH₃, and N(CH₃)₂; and

W is selected from O, S, SO, SO₂, and S(═O)(═NH); and

wherein

represents a double or a single bond, wherein all other variable are asdefined in the Summary of the Invention.

In Embodiments E1-E6 and sub-embodiments of Embodiments E1-E6, eachoccurrence of R⁸ is independently selected from H, halogen, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, —OC₁-C₆ alkyl, benzyl, —OCF₃,—OCHF₂, —OR³, ═O, —CN, —NO₂, —SR³, —SF₅, —SCF₃, —SOR³, —SO₂R³,—S(═O)(═N)R², —N(R²)₂, —NR²COR³, —SO₂N(R²)₂, —NR²SO₂R³, —COOH, —COR⁹,—COOR³, —CON(R²)₂, —CO(R²)₂ and —C(R⁹)₂N(R²)₂, wherein said C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, —OC₁-C₆ alkyl, and benzyl areoptionally substituted with up to four F, —OCH₃, —OH, ═O, NH₂, NHCH₃,SO₂R³, and N(CH₃)₂.

In a specific sub-embodiment of Embodiments E1-E6, one or moreoccurrences of R⁸ is selected from: —H, —OH, —CN, —CH₃, —CH₂NH₂, —CONH₂,C(CH₃)₂OH, —COOC(CH₃)₂CH₃, —SCH₃, —OCH₃, —C₁, —F, —CHF₂, ═O,-cyclopropyl, NO₂, —NHSO₂CH₃, —SO₂N(CH₃)₂, —S(═O)(═NH)CH₃, —SO₂CH₃,—SOCH₃, —SO₂NH₂, —OCH₂CH₂OH, COCH₃, COcyclopropyl and

In another specific sub-embodiment of Embodiments E1-E6, one or moreoccurrences of R⁸ is selected from:

—SOCH₃, —SO₂CH₃, oxo, —H, —SCH₃, —OH, —SO₂N(CH₃)₂, —SO₂NH₂, —CONH₂,—O(CH₂)₂OH, and —F.

A seventh embodiment (Embodiment E7) is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein, A is as defined inthe Summary of the Invention or in any of Embodiments E1-E6, E is a6-membered aryl, wherein said aryl is optionally substituted with up tofour substituents, which are independently selected from halogen, —CH₃,—SOCH₃, —SO₂CH₃, —H, —SCH₃, —OH, —SO₂N(CH₃)₂, —SO₂NH₂, —CONH₂ and—O(CH₂)₂OH, and all other variables are as defined in the Summary of theInvention.

An eighth embodiment (Embodiment E8) is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein, A is as defined inthe Summary of the Invention or in any of Embodiments E1-E6, E is a6-membered or 9-membered heterocycle containing from one to threeheteroatoms independently selected from S, O, and N, wherein saidheterocycle is unsubstituted or substituted with up to foursubstituents, which are independently selected from halogen, and ═O, andall other variables are as defined in the Summary of the Invention.

A ninth embodiment (Embodiment E9) is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein, A is as defined inthe Summary of the Invention or in any of Embodiments E1-E6, E is a6-membered heteroaryl containing from one to three heteroatomsindependently selected from S, O, and N, wherein said heteroaryl isoptionally substituted with up to four substituents, which areindependently selected from halogen, —CN, —CF₃, —CHF₂, —CH₂NH₂,—CH₂NHCOCH₃, —OCF₃, —OCHF₂, —OH, —O—(C₁-C₆)alkyl, C₁-C₆ alkyl, and C₃-C₆cycloalkyl, and all other variables are as defined in the Summary of theInvention.

A tenth embodiment (Embodiment E10) is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein, A is as defined inthe Summary of the Invention or in any of Embodiments E1-E6, E is:

and all other variables are as defined in the Summary of the Invention,or

and all other variables are as defined in the Summary of the Invention.

An eleventh embodiment (Embodiment E11) is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein, A is as defined inthe Summary of the Invention or in any of Embodiments E1-E6, E is:

and all other variables are as defined in the Summary of the Invention.

A twelfth embodiment (Embodiment E12) is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein, A is as defined inthe summary of the invention or in any of Embodiments E1-E6, E is:

and all other variables are as originally defined.

A thirteenth embodiment (Embodiment E13) is a compound of Formula IA, ora pharmaceutically acceptable salt thereof, having the formula:

wherein:

A is as defined in any of Embodiments E1-E6.

A fourteenth embodiment (Embodiment E14) is a compound of Formula IB, ora pharmaceutically acceptable salt thereof, having the formula:

wherein:

A is as defined in any of Embodiments E1-E6.

In sub-embodiments of Embodiments, A is:

wherein R⁸ represents one, two, three or four optional ring carbonsubstituents, which can be the same or different.

In sub-embodiments of Embodiments, R⁸ is —OH, —CN, —CH₃, —CH₂NH₂,—CONH₂, C(CH₃)₂OH, —COOC(CH₃)₂CH₃, —SCH₃, —OCH₃, —C₁, —F, —CHF₂, ═O,-cyclopropyl, NO₂, —NHSO₂CH₃, —SO₂N(CH₃)₂, —S(═O)(═NH)CH₃, —SO₂CH₃,—SOCH₃, —SO₂NH₂, —OCH₂CH₂OH, COCH₃, COcyclopropyl and

In sub-embodiments of Embodiments, A is:

wherein R⁸ represents one, two, three or four optional ring carbonsubstituents, which can be the same or different.

In sub-embodiments of Embodiments, R⁸ is halogen, —SOCH₃, —SO₂CH₃,—SONH₂, —H, —SCH₃, —OH, —SO₂N(CH₃)₂, —CONH₂ or —O(CH₂)₂OH.

In sub-embodiments of Embodiments, A is:

In sub-embodiments of Embodiments, A is:

wherein R⁸ represents one, two, three or four optional ring carbonsubstituents, which can be the same or different.

In sub-embodiments of Embodiments, R⁸ is halogen or —SO₂CH₃.

In sub-embodiments of Embodiments, A is:

In another aspect the present invention includes compounds, orpharmaceutically acceptable salts thereof, having the structure:

In another aspect the present invention includes compounds, orpharmaceutically acceptable salts thereof, having the structure:

In certain embodiments, the present invention includes compounds, orpharmaceutically acceptable salts thereof, having the structure:

Also described herein are prodrugs of the compounds of Formula I,represented by Formula II:

wherein embodiments of A and E are described above.

Also described herein are prodrugs of the compounds of Formula I,represented by Formula III:

wherein R20 is OH or —OP═O(OH)₂ and embodiments of A and E are describedabove.

Also described herein are the following of Formula IIA and IIB:

wherein the embodiments of A are described above.

Also described herein is the following compound:

Reference to different embodiments with respect to Formula I compounds,specifically includes different embodiments of Formula I such as FormulaIA and Formula IB, sub-embodiments of Formula IA and Formula IB, otherembodiments provided herein, and individual compounds described herein.

Other embodiments of the present invention include the following:

-   -   (a) A pharmaceutical composition comprising an effective amount        of a compound of Formula I, IA, IB or Formula II, IIA, IIB as        defined herein, or a pharmaceutically acceptable salt thereof,        and a pharmaceutically acceptable carrier.    -   (b) The pharmaceutical composition of (a), further comprising a        second compound, wherein the second compound is an antibiotic.    -   (c) The pharmaceutical composition of (b), wherein the second        compound is selected from the group consisting of: ethambutol,        pyrazinamide, isoniazid, levofloxacin, moxifloxacin,        gatifloxacin, ofloxacin, kanamycin, amikacin, capreomycin,        streptomycin, ethionamide, prothionamide, cycloserine,        terididone, para-aminosalicylic acid, clofazimine,        clarithromycin, amoxicillin-clavulanate, thiacetazone,        meropenem-clavulanate, GSK 3036656, M72/AS01E vaccine and        thioridazine.    -   (d) A pharmaceutical composition comprising (i) a compound of        Formula I, IA, IB or Formula II, IIA, IIB or a pharmaceutically        acceptable salt thereof, and (ii) a second compound, wherein the        second compound is an antibiotic, wherein the compound of        Formula I, IA, IB or Formula II, IIA, IIB and the second        compound are each employed in an amount that renders the        combination effective for treating or preventing bacterial        infection.    -   (e) The combination of (d), wherein the second compound is        selected from the group consisting of: ethambutol, pyrazinamide,        isoniazid, levofloxacin, moxifloxacin, gatifloxacin, ofloxacin,        kanamycin, amikacin, capreomycin, streptomycin, ethionamide,        prothionamide, cycloserine, terididone, para-aminosalicylic        acid, clofazimine, clarithromycin, amoxicillin-clavulanate,        thiacetazone, meropenem-clavulanate, and thioridazine.    -   (f) A method for treating a bacterial infection in a subject        which comprises administering to a subject in need of such        treatment an effective amount of a compound of Formula I, IA, IB        or Formula II, IIA, IIB or a pharmaceutically acceptable salt        thereof.    -   (g) A method for preventing and/or treating a bacterial        infection which comprises administering to a subject in need of        such treatment an effective amount of a compound of Formula I,        IA, IB or Formula II, IIA, IIB or a pharmaceutically acceptable        salt thereof.    -   (h) A method for treating a bacterial infection which comprises        administering to a subject in need of such treatment a        therapeutically effective amount of the composition of (a), (b),        (c), (d), or (e).    -   (i) The method of treating a bacterial infection as set forth in        (f), (g), or (h), wherein the bacterial infection is due to        Mycobacterium tuberculosis.    -   (j) A method for preventing and/or treating a mycobacterial        infection which comprises administering to a subject in need of        such treatment an effective amount of a composition comprising        an Oxazolidinone Compound, or a pharmaceutically acceptable salt        thereof.    -   (k) The method of treating a mycobacterial infection as set        forth in (j), wherein the mycobacterial infection is due to M.        tuberculosis.    -   (l) The method of treating a mycobacterial infection as set        forth in (j), wherein the composition is a composition of (a),        (b), (c), (d), or (e).    -   (m) The method of treating a bacterial infection as set forth in        (f), (g), or (h), wherein the bacterial infection is due to        Mycobacterium abscessus, Mycobacterium chelonae, Mycobacterium        fortuitum, Mycobacterium intracellulare, Mycobacterium kansasii,        Mycobacterium marinum and/or Mycobacterium avium.

The present invention also includes a compound of Formula I, IA, IB orFormula II, IIA, IIB or a pharmaceutically acceptable salt thereof, (i)for use in, (ii) for use as a medicament for, or (iii) for use in thepreparation (or manufacture) of a medicament for, medicine or treatingbacterial infection, particularly a mycobacterial infection. In theseuses, the compounds of the present invention can optionally be employedin combination with one or more second therapeutic agents includingethambutol, pyrazinamide, isoniazid, levofloxacin, moxifloxacin,gatifloxacin, ofloxacin, kanamycin, amikacin, capreomycin, streptomycin,ethionamide, prothionamide, cycloserine, terididone, para-aminosalicylicacid, clofazimine, clarithromycin, amoxicillin-clavulanate,thiacetazone, meropenem-clavulanate, GSK 3036656, M72/AS01E vaccine andthioridazine.

Additional embodiments of the invention include the pharmaceuticalcompositions, combinations and methods set forth in (a)-(l) above andthe uses set forth in the preceding paragraph, wherein the compound ofthe present invention employed therein is a compound of one of theembodiments, sub-embodiments, classes or sub-classes described above.The compound may optionally be used in the form of a pharmaceuticallyacceptable salt in these embodiments.

In the embodiments of the compounds and salts provided above, it is tobe understood that each embodiment may be combined with one or moreother embodiments, to the extent that such a combination provides astable compound or salt and is consistent with the description of theembodiments. It is further to be understood that the embodiments ofcompositions and methods provided as (a) through (l) above areunderstood to include all embodiments of the compounds and/or salts,including such embodiments as result from combinations of embodiments.

Additional embodiments of the present invention include each of thepharmaceutical compositions, combinations, methods and uses set forth inthe preceding paragraphs, wherein the compound of the present inventionor its salt employed therein is substantially pure. With respect to apharmaceutical composition comprising a compound of Formula I, IA, or IBor its salt and a pharmaceutically acceptable carrier and optionally oneor more excipients, it is understood that the term “substantially pure”is in reference to a compound of Formula I, IA, or IB or its salt perse; i.e., the purity of the active ingredient in the composition.

Definitions and Abbreviations

The terms used herein have their ordinary meaning and the meaning ofsuch terms is independent at each occurrence thereof. Thatnotwithstanding and except where stated otherwise, the followingdefinitions apply throughout the specification and claims. Chemicalnames, common names, and chemical structures may be used interchangeablyto describe the same structure. If a chemical compound is referred tousing both a chemical structure and a chemical name and an ambiguityexists between the structure and the name, the structure predominates.These definitions apply regardless of whether a term is used by itselfor in combination with other terms, unless otherwise indicated. Hence,the definition of “alkyl” applies to “alkyl” as well as the “alkyl”portions of “hydroxyalkyl,” “haloalkyl,” “—O-alkyl,” etc. . . . .

As used herein, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Alkyl” means saturated carbon chains which may be linear or branched orcombinations thereof, unless the carbon chain is defined otherwise.Other groups having the prefix “alk”, such as alkoxy and alkanoyl, alsomay be linear or branched, or combinations thereof, unless the carbonchain is defined otherwise. Examples of alkyl groups include methyl,ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl,heptyl, octyl, and the like.

“Alkenyl” means carbon chains which contain at least one carbon-carbondouble bond, and which may be linear or branched, or combinationsthereof, unless otherwise defined. Examples of alkenyl include vinyl,allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl,2-methyl-2-butenyl, and the like.

“Antibiotic” refers to a compound or composition which decreases theviability of a microorganism, or which inhibits the growth orproliferation of a microorganism. The phrase “inhibits the growth orproliferation” means increasing the generation time (i.e., the timerequired for the bacterial cell to divide or for the population todouble) by at least about 2-fold. Preferred antibiotics are those whichcan increase the generation time by at least about 10-fold or more(e.g., at least about 100-fold or even indefinitely, as in total celldeath). As used in this disclosure, an antibiotic is further intended toinclude an antimicrobial, bacteriostatic, or bactericidal agent.

“About”, when modifying the quantity (e.g., kg, L, or equivalents) of asubstance or composition, or the value of a physical property, or thevalue of a parameter characterizing a process step (e.g., thetemperature at which a process step is conducted), or the like refers tovariation in the numerical quantity that can occur, for example, throughtypical measuring, handling and sampling procedures involved in thepreparation, characterization and/or use of the substance orcomposition; through inadvertent error in these procedures; throughdifferences in the manufacture, source, or purity of the ingredientsemployed to make or use the compositions or carry out the procedures;and the like. In certain embodiments, “about” can mean a variation of±0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 3.0, 4.0, or 5.0 of the appropriateunit. In certain embodiments, “about” can mean a variation of ±1%, 2%,3%, 4%, 5%, 10%, or 20%.

“Aromatic ring system” means monocyclic, bicyclic or tricyclic aromaticring or ring system containing 5-14 ring atoms, wherein at least one ofthe rings is aromatic. Aromatic ring systems, as used herein, encompassaryls and heteroaryls. The term may be used to describe a carbocyclicring fused to an aryl group. For example, a 5-7-membered cycloalkyl canbe fused through two adjacent ring atoms to a 5-6-membered heteroarylcontaining 1, 2, or 3 heteroatom ring atoms selected from N, O, and S.In another example, a heteromonocyclic ring is fused through two ringatoms to a phenyl or 5-6-membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S.

“Aryl” means a monocyclic, bicyclic or tricyclic carbocyclic aromaticring or ring system containing 6-14 carbon atoms, wherein at least oneof the rings is aromatic. Examples of aryl include phenyl and naphthyl.

“Cycloalkyl” means a saturated monocyclic, bicyclic or bridgedcarbocyclic ring, having a specified number of carbon atoms. Examples ofcycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andthe like.

The term “heterocycloalkyl,” as used herein, refers to a non-aromaticsaturated monocyclic or multicyclic ring system comprising 3 to 11 ringatoms, wherein from 1 to 4 of the ring atoms are independently O, S, orN, and the remainder of the ring atoms are carbon atoms. Aheterocycloalkyl group can be joined via a ring carbon or ring nitrogenatom (if present). In one embodiment, a heterocycloalkyl group ismonocyclic and has from about 3 to about 7 ring atoms. In anotherembodiment, a heterocycloalkyl group is monocyclic has from about 4 toabout 7 ring atoms. In another embodiment, a heterocycloalkyl group isbicyclic and has from about 7 to about 11 ring atoms. In still anotherembodiment, a heterocycloalkyl group is monocyclic and has 5 or 6 ringatoms. In one embodiment, a heterocycloalkyl group is monocyclic. Inanother embodiment, a heterocycloalkyl group is bicyclic. There are noadjacent oxygen and/or sulfur atoms present in the ring system. Any —NHgroup in a heterocycloalkyl ring may exist protected such as, forexample, as an —N(BOC), —N(Cbz), —N(Tos) group and the like; suchprotected heterocycloalkyl groups are considered part of this invention.The term “heterocycloalkyl” also encompasses a heterocycloalkyl group,as defined above, which is fused to an aryl (e.g., benzene) orheteroaryl ring. A heterocycloalkyl group can be optionally substitutedby one or more “ring system substituents” which may be the same ordifferent, and are as defined herein below. The nitrogen or sulfur atomof the heterocycloalkyl (if present) can be optionally oxidized to thecorresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples ofmonocyclic heterocycloalkyl rings include oxetanyl, piperidyl,pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, delta-lactam,delta-lactone, silacyclopentane, tetrahydro-2H-thiopyran 1,1-dioxide,silapyrrolidine and the like, and all isomers thereof.

As used herein, e.g. in the definition of R⁸, “—CONH₂” means “—C═ONH₂”.

“Drug resistant” means, in connection with a Mycobacterium, aMycobacterium which is no longer susceptible to at least one previouslyeffective drug; which has developed the ability to withstand antibioticattack by at least one previously effective drug. A drug resistantstrain may relay that ability to withstand to its progeny. Saidresistance may be due to random genetic mutations in the bacterial cellthat alters its sensitivity to a single drug or to different drugs.

“Halogen” includes fluorine, chlorine, bromine and iodine.

“Heteroaryl”, as used herein, refers to an monocyclic or multicyclicring system comprising about 5 to about 14 ring atoms, wherein from 1 to4 of the ring atoms is independently O, N, or S and the remaining ringatoms are carbon atoms, wherein at least one of the heteroatomcontaining rings is aromatic. In one embodiment, a heteroaryl group has5 to 10 ring atoms. In another embodiment, a heteroaryl group ismonocyclic and has 5 or 6 ring atoms. In another embodiment, aheteroaryl group is bicyclic. A heteroaryl group can be optionallysubstituted by one or more “ring system substituents” which may be thesame or different, and are as defined herein below. A heteroaryl groupis joined via a ring carbon atom, and any nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. The term“heteroaryl” also encompasses a heteroaryl group, as defined above,which is fused to a benzene ring. Non-limiting examples of heteroarylsinclude pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone(including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl,oxadiazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl,benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,quinolinyl, imidazolyl, benzimidazolyl, thienopyridyl, quinazolinyl,thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl,benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like, and allisomeric forms thereof. In another embodiment of the present invention,heteroaryl is pyridine. Examples of bicyclic rings include:

“Heterocycle” means a monocyclic or bicyclic saturated, partiallyunsaturated, or unsaturated ring system containing 5-10 atoms andcontaining at least one ring heteroatom selected from N, S and O. Inselect embodiments, the ring system contains 1-4 heteroatoms selectedfrom N, S and O. When a heterocycle contains two rings, the rings may befused, bridged or spirocyclic. Examples of monocyclic heterocycle ringsinclude piperazine, piperidine, and morpholine. Examples of bicyclicheterocycle rings include 1,4-diazabicyclo[2,2,2]octane and2,6-diazaspiroheptane. Heterocycles include heteroaryls andheterocycloalkyls.

“Oxo” means an oxygen atom connected to another atom by a double bondand is can be represented “=0”.

“Tuberculosis” comprises disease states usually associated withinfections caused by mycobacteria species comprising M. tuberculosiscomplex. The term “tuberculosis” is also associated with mycobacterialinfections caused by mycobacteria other than M. tuberculosis (MOTT).Other mycobacterial species include M. avium-intracellulare, M.kansarii, M. fortuitum, M. chelonae, M. leprae, M. africanum, and M.microti, M. avium paratuberculosis, M. intracellulare, M. scrofulaceum,M. abscessus, M. avium, M. xenopi, M. marinum, and M. ulcerans. Anotherembodiment of the present invention is a compound of Formula I, IA, IBor a pharmaceutically acceptable salt thereof, as originally defined oras defined in any of the foregoing embodiments, sub-embodiments,aspects, classes or sub-classes, wherein the compound or its salt is ina substantially pure form. As used herein “substantially pure” meanssuitably at least about 60 wt. %, typically at least about 70 wt. %,preferably at least about 80 wt. %, more preferably at least about 90wt. % (e.g., from about 90 wt. % to about 99 wt. %), even morepreferably at least about 95 wt. % (e.g., from about 95 wt. % to about99 wt. %, or from about 98 wt. % to 100 wt. %), and most preferably atleast about 99 wt. % (e.g., 100 wt. %) of a product containing acompound of Formula I, IA, or IB or a salt of Formula I, IA, or IB(e.g., the product isolated from a reaction mixture affording thecompound or salt) consists of the compound or salt. The level of purityof the compounds and salts can be determined using a standard method ofanalysis such as thin layer chromatography, gel electrophoresis, highperformance liquid chromatography, and/or mass spectrometry. If morethan one method of analysis is employed and the methods provideexperimentally significant differences in the level of puritydetermined, then the method providing the highest level of puritygoverns. A compound or salt of 100% purity is one which is free ofdetectable impurities as determined by a standard method of analysis.With respect to a compound of the invention which has one or moreasymmetric centers and can occur as mixtures of stereoisomers, asubstantially pure compound can be either a substantially pure mixtureof the stereoisomers or a substantially pure individual diastereomer orenantiomer.

The present invention encompasses all stereoisomeric forms of thecompounds of Formula I, Formula IA and Formula IB. Unless a specificstereochemistry is indicated, the present invention is meant tocomprehend all such isomeric forms of these compounds. Centers ofasymmetry that are present in the compounds of Formula I, Formula IA,and Formula IB can all independently of one another have (R)configuration or (S) configuration. When bonds to the chiral carbon aredepicted as straight lines in the structural Formulas of the invention,it is understood that both the (R) and (S) configurations of the chiralcarbon, and hence both enantiomers and mixtures thereof, are embracedwithin the Formula. Similarly, when a compound name is recited without achiral designation for a chiral carbon, it is understood that both the(R) and (S) configurations of the chiral carbon, and hence individualenantiomers and mixtures thereof, are embraced by the name. Theproduction of specific stereoisomers or mixtures thereof may beidentified in the Examples where such stereoisomers or mixtures wereobtained, but this in no way limits the inclusion of all stereoisomersand mixtures thereof from being within the scope of this invention.

The invention includes all possible enantiomers and diastereomers andmixtures of two or more stereoisomers, for example mixtures ofenantiomers and/or diastereomers, in all ratios. Thus, enantiomers are asubject of the invention in enantiomerically pure form, both aslevorotatory and as dextrorotatory antipodes, in the form of racematesand in the form of mixtures of the two enantiomers in all ratios. In thecase of a cis/trans isomerism the invention includes both the cis formand the trans form as well as mixtures of these forms in all ratios. Thepreparation of individual stereoisomers can be carried out, if desired,by separation of a mixture by customary methods, for example bychromatography or crystallization, by the use of stereochemicallyuniform starting materials for the synthesis or by stereoselectivesynthesis. Optionally a derivatization can be carried out before aseparation of stereoisomers. The separation of a mixture ofstereoisomers can be carried out at an intermediate step during thesynthesis of a compound of Formula I, Formula IA, or Formula IB or itcan be done on a final racemic product. Absolute stereochemistry may bedetermined by X-ray crystallography of crystalline products orcrystalline intermediates which are derivatized, if necessary, with areagent containing a stereogenic center of known configuration. Wherecompounds of this invention are capable of tautomerization, allindividual tautomers as well as mixtures thereof are included in thescope of this invention. Unless a particular isomer, salt, solvate(including hydrates) or solvated salt of such racemate, enantiomer,diastereomer or tautomer is indicated, the present invention includesall such isomers, as well as salts, solvates (including hydrates) andsolvated salts of such racemates, enantiomers, diastereomers andtautomers and mixtures thereof.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described last,preceded by the adjacent functionality toward the point of attachment.

In choosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e. R², R³, etc.,are to be chosen in conformity with well-known principles of chemicalstructure connectivity and stability.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. The term substituted shall be deemed to includemultiple degrees of substitution by a named substituent. Where multiplesubstituent moieties are disclosed or claimed, the substituted compoundcan be independently substituted by one or more of the disclosed orclaimed substituent moieties, singly or plurally. By independentlysubstituted, it is meant that the (two or more) substituents can be thesame or different.

By “stable compound” or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and whose structure and properties remain orcan be caused to remain essentially unchanged for a period of timesufficient to allow use of the compound for the purposes describedherein (e.g., therapeutic administration to a subject). The compounds ofthe present invention are limited to stable compounds embraced byFormula I, IA and IB.

When a group, e.g., C₁-C₈ alkyl, is indicated as being substituted, suchsubstitutions can also occur where such group is part of a largersubstituent, e.g., —C₁-C₆alkyl-C₃-C₇cycloalkyl and —C₁-C₈alkyl-aryl.

In the compounds of Formula I, IA, and IB, the atoms may exhibit theirnatural isotopic abundances, or one or more of the atoms may beartificially enriched in a particular isotope having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number predominantly found in nature. The present invention ismeant to include all suitable isotopic variations of the compounds ofFormula I, IA, and IB. For example, different isotopic forms of hydrogen(H) include protium (¹H) and deuterium (²H or D). Protium is thepredominant hydrogen isotope found in nature. Enriching for deuteriummay afford certain therapeutic advantages, such as increasing in vivohalf-life or reducing dosage requirements, or may provide a compounduseful as a standard for characterization of biological samples.Isotopically-enriched compounds within Formula I, IA, and IB can beprepared without undue experimentation by conventional techniques wellknown to those skilled in the art or by processes analogous to thosedescribed in the EXAMPLES herein using appropriate isotopically-enrichedreagents and/or intermediates.

Unless expressly stated to the contrary in a particular context, any ofthe various cyclic rings and ring systems described herein may beattached to the rest of the compound at any ring atom (i.e., any carbonatom or any heteroatom) provided that a stable compound results.

Unless expressly stated to the contrary, all ranges cited herein areinclusive. For example, a heteroaromatic ring described as containingfrom “1 to 4 heteroatoms” means the ring can contain 1, 2, 3 or 4heteroatoms. It is also to be understood that any range cited hereinincludes within its scope all of the sub-ranges within that range. Thus,for example, a heterocyclic ring described as containing from “1 to 4heteroatoms” is intended to include as aspects thereof, heterocyclicrings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2heteroatoms, 3 heteroatoms, and 4 heteroatoms. Similarly, C₁₋₆ when usedwith a chain, for example an alkyl chain, means that the chain cancontain 1, 2, 3, 4, 5 or 6 carbon atoms. It also includes all rangescontained therein including C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆, C₃₋₆, C₄₋₆,C₅₋₆, and all other possible combinations.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

When any substituent or variable (e.g., alkyl, R⁸, R¹¹, etc.) occursmore than one time in any constituent or in Formula (I), its definitionon each occurrence is independent of its definition at every otheroccurrence, unless otherwise indicated. Also, combinations ofsubstituents and/or variables are permissible only if such combinationsresult in stable compounds. A squiggly line across a bond in asubstituent variable represents the point of attachment.

The term “compound” refers to the free compound and, to the extent theyare stable, any hydrate or solvate thereof. A hydrate is the compoundcomplexed with water, and a solvate is the compound complexed with anorganic solvent.

As indicated above, the compounds of the present invention can beemployed in the form of pharmaceutically acceptable salts. It will beunderstood that, as used herein, the compounds of the instant inventioncan also include the pharmaceutically acceptable salts, and also saltsthat are not pharmaceutically acceptable when they are used asprecursors to the free compounds or their pharmaceutically acceptablesalts or in other synthetic manipulations.

The term “pharmaceutically acceptable salt” refers to a salt whichpossesses the effectiveness of the parent compound and which is notbiologically or otherwise undesirable (e.g., is neither toxic norotherwise deleterious to the recipient thereof). The term“pharmaceutically acceptable salt” refers to salts prepared frompharmaceutically acceptable non-toxic bases or acids including inorganicor organic bases and inorganic or organic acids. Salts of basiccompounds encompassed within the term “pharmaceutically acceptable salt”refer to non-toxic salts of the compounds of this invention which aregenerally prepared by reacting the free base with a suitable organic orinorganic acid. Representative salts of basic compounds of the presentinvention include, but are not limited to, the following: acetate,ascorbate, adipate, alginate, aspirate, benzenesulfonate, benzoate,bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate,camphorate, camphorsulfonate, camsylate, carbonate, chloride,clavulanate, citrate, cyclopentane propionate, diethylacetic,digluconate, dihydrochloride, dodecylsulfanate, edetate, edisylate,estolate, esylate, ethanesulfonate, formic, fumarate, gluceptate,glucoheptanoate, gluconate, glutamate, glycerophosphate,glycollylarsanilate, hemisulfate, heptanoate, hexanoate,hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,2-hydroxyethanesulfonate, hydroxynaphthoate, iodide, isonicotinic,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, methanesulfonate,mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate,N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate),palmitate, pantothenate, pectinate, persulfate, phosphate/diphosphate,pimelic, phenylpropionic, polygalacturonate, propionate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,thiocyanate, tosylate, triethiodide, trifluoroacetate, undeconate,valerate and the like. Furthermore, where the compounds of the inventioncarry an acidic moiety, suitable pharmaceutically acceptable saltsthereof include, but are not limited to, salts derived from inorganicbases including aluminum, ammonium, calcium, copper, ferric, ferrous,lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, andthe like. Particularly preferred are the ammonium, calcium, magnesium,potassium, and sodium salts. Salts derived from pharmaceuticallyacceptable organic non-toxic bases include salts of primary, secondary,and tertiary amines, cyclic amines, dicyclohexyl amines and basicion-exchange resins, such as arginine, betaine, caffeine, choline,N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like. Also, included are the basicnitrogen-containing groups may be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl;and diamyl sulfates, long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethyl bromides and others.

These salts can be obtained by known methods, for example, by mixing acompound of the present invention with an equivalent amount and asolution containing a desired acid, base, or the like, and thencollecting the desired salt by filtering the salt or distilling off thesolvent. The compounds of the present invention and salts thereof mayform solvates with a solvent such as water, ethanol, or glycerol. Thecompounds of the present invention may form an acid addition salt and asalt with a base at the same time according to the type of substituentof the side chain.

The compounds of the invention can also be employed in the form of aprodrug. For example, the hydrogen in —COOH be replaced with any thefollowing groups: C₁₋₆ alkyl, C₃₋₆ cycloalkyl,—C₁₋₆alkyl-C₃₋₆cycloalkyl, C₃₋₇ cycloheteroalkyl,—C₁₋₆alkyl-C₃₋₇cycloheteroalkyl, aryl, —C₁₋₁₀alkyl-aryl, heteroaryl, and—C₁₋₁₀ alkyl-heteroaryl. Any C₁₋₆ alkyl, C₃₋₆ cycloalkyl, or C₃₋₇cycloheteroalkyl can also be substituted. Any aryl or heteroaryl canalso be substituted as indicated.

As set forth above, the present invention includes pharmaceuticalcompositions comprising a compound of Formula I, IA, or IB of thepresent invention, optionally one or more other active components, and apharmaceutically acceptable carrier. The characteristics of the carrierwill depend on the route of administration. By “pharmaceuticallyacceptable” is meant that the ingredients of the pharmaceuticalcomposition must be compatible with each other, do not interfere withthe effectiveness of the active ingredient(s), and are not deleterious(e.g., toxic) to the recipient thereof. Thus, compositions according tothe invention may, in addition to the inhibitor, contain diluents,fillers, salts, buffers, stabilizers, solubilizers, and other materialswell known in the art.

Also as set forth above, the present invention includes a method fortreating a bacterial infection which comprises administering to asubject in need of such treatment a therapeutically effective amount ofa compound of Formula I, IA, or IB or a pharmaceutically acceptable saltthereof. The term “subject” (or, alternatively, “patient”) as usedherein refers to an animal, preferably a mammal, most preferably ahuman, who has been the object of treatment, observation or experiment.The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of Formula I, IA or IB meanproviding the compound, or a pharmaceutically acceptable salt thereof,to the individual in need of treatment. When a compound or a saltthereof is provided in combination with one or more other active agents,“administration” and its variants are each understood to includeprovision of the compound or its salt and the other agents at the sametime or at different times. When the agents of a combination areadministered at the same time, they can be administered together in asingle composition or they can be administered separately. It isunderstood that a “combination” of active agents can be a singlecomposition containing all of the active agents or multiple compositionseach containing one or more of the active agents. In the case of twoactive agents a combination can be either a single compositioncomprising both agents or two separate compositions each comprising oneof the agents; in the case of three active agents a combination can beeither a single composition comprising all three agents, three separatecompositions each comprising one of the agents, or two compositions oneof which comprises two of the agents and the other comprises the thirdagent; and so forth.

The compositions and combinations of the present invention are suitablyadministered in effective amounts. The term “effective amount” as usedherein with respect to an oxazolidinone compound means the amount ofactive compound sufficient to cause a bacteriocidal or bacteriostaticeffect. In one embodiment, the effective amount is a “therapeuticallyeffective amount” meaning the amount of active compound that canovercome bacterial drug resistance and which is sufficient to inhibitbacterial replication and/or result in bacterial killing. When theactive compound (i.e., active ingredient) is administered as the salt,references to the amount of active ingredient are to the free acid orfree base form of the compound.

The administration of a composition of the present invention is suitablyparenteral, oral, sublingual, transdermal, topical, intranasal,intratracheal, intraocular, or intrarectal, wherein the composition issuitably formulated for administration by the selected route usingformulation methods well known in the art, including, for example, themethods for preparing and administering formulations described inchapters 39, 41, 42, 44 and 45 in Remington—The Science and Practice ofPharmacy, 21^(st) edition, 2006. In one embodiment, compounds of theinvention are administered intravenously in a hospital setting. Inanother embodiment, administration is oral in the form of a tablet orcapsule or the like. The dosage of the compounds of the invention and oftheir pharmaceutically acceptable salts may vary within wide limits andshould naturally be adjusted, in each particular case, to the individualconditions and to the pathogenic agent to be controlled. In general, fora use in the treatment of bacterial infections, the daily dose may bebetween 0.005 mg/kg to 100 mg/kg, 0.01 mg/kg to 10 mg/kg, 0.05 mg/kg to5 mg/kg, 0.05 mg/kg to 1 mg/kg.

In some embodiments, the compound of the invention is provided in apharmaceutical formulation for oral, intravenous, intramuscular, nasal,or topical administration. Thus, in some embodiments, the formulationcan be prepared in a dosage form, such as but not limited to, a tablet,capsule, liquid (solution or suspension), suppository, ointment, cream,or aerosol. In some embodiments, the presently disclosed subject matterprovides such compounds and/or formulations that have been lyophilizedand that can be reconstituted to form pharmaceutically acceptableformulations for administration, for example, as by intravenous orintramuscular injection.

Intravenous administration of a compound of the invention can beconducted by reconstituting a powdered form of the compound with anacceptable solvent. Suitable solvents include, for example, salinesolutions (e.g., 0.9% Sodium Chloride Injection) and sterile water(e.g., Sterile Water for Injection, Bacteriostatic Water for Injectionwith methylparaben and propylparaben, or Bacteriostatic Water forInjection with 0.9% benzyl alcohol). The powdered form of the compoundcan be obtained by gamma-irradiation of the compound or bylyophilization of a solution of the compound, after which the powder canbe stored (e.g., in a sealed vial) at or below room temperature until itis reconstituted. The concentration of the compound in the reconstitutedIV solution can be, for example, in a range of from about 0.1 mg/mL toabout 20 mg/mL.

The methods of the presently disclosed subject matter are useful fortreating these conditions in that they inhibit the onset, growth, orspread of the condition, cause regression of the condition, cure thecondition, or otherwise improve the general well-being of a subjectafflicted with, or at risk of, contracting the condition. Thus, inaccordance with the presently disclosed subject matter, the terms“treat”, “treating”, and grammatical variations thereof, as well as thephrase “method of treating”, are meant to encompass any desiredtherapeutic intervention, including but not limited to a method fortreating an existing infection in a subject, and a method for theprophylaxis (i.e., preventing) of infection, such as in a subject thathas been exposed to a microbe as disclosed herein or that has anexpectation of being exposed to a microbe as disclosed herein.

Infections that may be treatable by the compounds of the invention canbe caused by a variety of microbes, including fungi, algae, protozoa,bacteria, and viruses. In some embodiments, the infection is a bacterialinfection. Exemplary microbial infections that may be treated by themethods of the invention include, but are not limited to, infectionscaused by one or more of Staphylococcus aureaus, Enterococcus faecalis,Bacillus anthracis, a Streptococcus species (e.g., Streptococcuspyogenes and Streptococcus pneumoniae), Escherichia coli, Pseudomonasaeruginosa, Burkholderia cepacia, a Proteus species (e.g., Proteusmirabilis and Proteus vulgaris), Klebsiella pneumoniae, Acinetobacterbaumannii, Strenotrophomonas maltophillia, Mycobacterium tuberculosis,Mycobacterium bovis, other mycobacteria of the tuberculosis complex, andnon-tuberculous mycobacteria, including Mycobacterium ulcerans,Mycobacterium abscessus, and Mycobacterium avium.

In certain embodiments, the infection is an infection of a gram-positivebacterium. In some embodiments, the infection is selected from amycobacterial infection, a Bacillus anthracis infection, an Enterococcusfaecalis infection, and a Streptococcus pneumoniae infection.

In some embodiments, the compound of Formula I, IA, or IB isadministered prophylactically to prevent or reduce the incidence of oneof: (a) a Mycobacterium tuberculosis infection in a subject at risk ofinfection; (b) a recurrence of a Mycobacterium tuberculosis infection;and (c) combinations thereof. In some embodiments, the compound ofFormula I, IA, or IB is administered to treat an existing Mycobacteriumtuberculosis infection. In some embodiments, the compound of Formula I,IA, or IB is administered to treat an infection of a multi-drugresistant strain of Mycobacterium tuberculosis (i.e., a strain that isresistant to two or more previously known anti-tuberculosis drugs, suchas isoniazid, ethambutol, rifampicin, kanamycin, capreomycin, linezolid,and streptomycin). In some embodiments, the compound of Formula (I) hasa minimum inhibitory concentration (MIC) against Mycobacteriumtuberculosis of 25 μg/mL or less. In some embodiments, the compound ofFormula I, IA or IB is administered to treat an infection of amulti-drug resistant strain of Mycobacterium tuberculosis.

Thus, the methods of the presently disclosed subject matter can beuseful for treating tuberculosis in that they inhibit the onset, growth,or spread of a TB infection, cause regression of the TB infection, curethe TB infection, or otherwise improve the general well-being of asubject afflicted with, or at risk of, contracting tuberculosis.

Subjects suffering from an M. tuberculosis or other tuberculosis-relatedinfection can be determined via a number of techniques, e.g., sputumsmear, chest X-ray, tuberculin skin test (i.e., Mantoux test or PPDtest) and/or the presence of other clinical symptoms (e.g., chest pain,coughing blood, fever, night sweats, appetite loss, fatigue, etc.). Ifdesired, bacterial RNA, DNA or proteins can be isolated from a subjectbelieved to be suffering from TB and analyzed via methods known in theart and compared to known nucleic or amino acid sequences of bacterialRNA, DNA or protein.

In some embodiments, the compound of Formula I, IA, or IB has a minimuminhibitory concentration (MIC) against Mycobacterium tuberculosis of 25μg/mL or less. MICS can be determined via methods known in the art, forexample, as described in Hurdle et al., 2008, J. Antimicrob. Chemother.62:1037-1045.

In some embodiments, the methods of the invention further compriseadministering to the subject an additional therapeutic compound. In someembodiments, the compound of the invention is administered to thesubject before, after, or at the same time as one or more additionaltherapeutic compounds. In some embodiments, the additional therapeuticcompound is an antibiotic. In some embodiments, the additionaltherapeutic compound is an anti-tuberculosis therapeutic. In someembodiments, the additional therapeutic compound is selected from thegroup comprising isoniazid, ethambutol, rifampicin, kanamycin,capreomycin, linezolid, and streptomycin.

The invention thus provides in a further aspect, a combinationcomprising a compound of Formula I, IA, or IB or a pharmaceuticallyacceptable salt thereof, together with one or more additionaltherapeutic agents. Examples of such one or more additional therapeuticagents are anti-tuberculosis agents including, but not limited to,amikacin, aminosalicylic acid, capreomycin, cycloserine, ethambutol,ethionamide, isoniazid, kanamycin, pyrazinamide, rifamycins (such asrifampin, rifapentine and rifabutin), streptomycin, clarithromycin,azithromycin, oxazolidinones and fluoroquinolones (such as ofloxacin,ciprofloxacin, moxifloxacin and gatifloxacin). Such chemotherapy isdetermined by the judgment of the treating physician using preferreddrug combinations. “First-line” chemotherapeutic agents used to treat aMycobacterium tuberculosis infection that is not drug resistant includeisoniazid, rifampin, ethambutol, streptomycin and pyrazinamide.“Second-line” chemotherapeutic agents used to treat a Mycobacteriumtuberculosis infection that has demonstrated drug resistance to one ormore “first-line” drugs include ofloxacin, ciprofloxacin, ethionamide,aminosalicylic acid, cycloserine, amikacin, kanamycin and capreomycin.In addition to the aforementioned, there are a number of newanti-tuberculosis therapeutic agents emerging from clinical studies thatmay also be employed as the one or more additional therapeutic agents ina combination with a compound of Formula I, IA, or IB including, but notlimited to, TMC-207, OPC-67683, PA-824, LL-3858 and SQ-109.

Thus, the other antibiotic which may be combined with the compounds ofFormula I, IA, IB or Formula II, IIA, IIB are for example rifampicin(rifampin); isoniazid; pyrazinamide; amikacin; ethionamide;moxifloxacin; ethambutol; streptomycin; para-aminosalicylic acid;cycloserine; capreomycin; kanamycin; thioacetazone;quinolones/fluoroquinolones such as for example ofloxacin,ciprofloxacin, sparfloxacin; macrolides such as for exampleclarithromycin, clofazimine, amoxicillin with clavulanic acid;rifamycins; rifabutin; rifapentine.

In a further aspect, the one or more additional therapeutic agent is,for example, an agent useful for the treatment of tuberculosis in amammal, therapeutic vaccines, anti-bacterial agents, anti-viral agents;antibiotics and/or agents for the treatment of HIV/AIDS. Examples ofsuch therapeutic agents include isoniazid (INH), ethambutol, rifampin,pirazinamide, streptomycin, capreomycin, ciprofloxacin and clofazimine.

In one aspect, the one or more additional therapeutic agent is atherapeutic vaccine. A compound of Formula I, IA, or IB or apharmaceutically acceptable salt thereof, may thus be administered inconjunction with vaccination against mycobacterial infection, inparticular vaccination against Mycobacterium tuberculosis infection.Existing vaccines against mycobacterial infection include BacillusCalmette Guerin (BCG). Vaccines currently under development for thetreatment, prophylaxis or amelioration of mycobacterial infectioninclude: modified BCG strains which recombinantly express additionalantigens, cytokines and other agents intended to improve efficacy orsafety; attenuated mycobacteria which express a portfolio of antigensmore similar to Mycobacterium tuberculosis than BCG; and subunitvaccines. Subunit vaccines may be administered in the form of one ormore individual protein antigens, or a fusion or fusions of multipleprotein antigens, either of which may optionally be adjuvanted, or inthe form of a polynucleotide encoding one or more individual proteinantigens, or encoding a fusion or fusions of multiple protein antigens,such as where the polynucleotide is administered in an expressionvector. Examples of subunit vaccines include, but are not limited to:M72, a fusion protein derived from the antigens Mtb32a and Mtb39;HyVac-1, a fusion protein derived from antigen 85b and ESAT-6; HyVac-4,a fusion protein derived from antigen 85b and Tb10.4; MVA85a, a modifiedvaccinia virus Ankara expressing antigen 85a; and Aeras-402, adenovirus35 expressing a fusion protein derived from antigen 85a, antigen 85b andTb10.4.

Abbreviations employed herein include the following:

ACN=acetonitrile; CBZ-Cl=benzyl chloroformate; CDCl₃=deuteratedchloroform; DCM=dichloromethane; DIAD=diisopropyl diazodicarboxylate,DIEA=N,N-Diisopropylethylamine; DMF=N,N-dimethylformamide; DMSO=dimethylsulfoxide; Et=ethyl; EtOAc=ethyl acetate; EtOH=ethanol; GFP=greenfluorescent protein;HATU=(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate), HET=heterocycle; H₂=hydrogen gas,HPLC=high-performance liquid chromatography; LC-MS=liquidchromatography/mass spectrometry; Me=methyl; MeOH=methanol; MIC=minimuminhibitory concentration; MW=molecular weight; MS=mass spectrometry;Mtb=Mycobacterium tuberculosis; Pd—C=palladium on carbon; RT=roomtemperature; TB=tuberculosis; TEA=triethylamine; TFA=trifluoroaceticacid; THF=tetrahydrofuran; and TBDMS=tert-butyl dimethylsilyl.

Methods for Making the Compounds of Formula (I):

The compounds of Formula (I) can be prepared according to the followingreaction schemes and EXAMPLES, or modifications thereof, using readilyavailable starting materials, reagents and conventional synthesisprocedures. In these reactions, it is also possible to make use ofvariations which are themselves known to those of ordinary skill in thisart, but are not mentioned in greater detail. Alternative syntheticpathways and analogous structures will be apparent to those skilled inthe art of organic synthesis in light of the following reaction schemesand EXAMPLES.

EXAMPLES Example 1 Synthesis of(5R)-3-[2-fluoro-4′-(methylsulfonyl)biphenyl-4-yl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one

Step A: Synthesis of(5R)-3-[2-fluoro-4′-(methylsulfonyl)biphenyl-4-yl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one

(5R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one(171.8 g, 592.2 mmol, 1 equiv), (4-methanesulfonylphenyl)boronic acid(130.4 g, 651.9 mmol, 1.10 equiv), potassium carbonate (163 g, 1179mmol, 1.99 equiv), THF (1750 mL), water (580 mL), and[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(dppf)Cl₂) (21.6 g, 29.52 mmol, 0.05 equiv) were placed into a 5-L4-necked round-bottom flask, purged and maintained with an inertatmosphere of nitrogen. The reaction mixture was warmed to 70° C. andallowed to stir at that temperature for 16 h. The reaction mixture wascooled to ambient temperature, filtered, and the precipitate wascollected. The precipitate was then dissolved in DMSO (1700 mL). Silicagel (27 g) was added, and the resulting mixture was warmed to 40° C. andallowed to stir at that temperature for 16 h. The mixture was filtered.Water (684 mL) was added to the filtrate, and the resulting mixturefiltered. The solids were collected and dried under reduced pressure toafford the title compound. MS (ESI) m/z: 364.0 [M+H⁺]; ¹H NMR (400 MHz,DMSO-d₆): δ 8.03 (d, J=8.3 Hz, 2H), 7.87-7.80 (m, 2H), 7.73-7.63 (m,2H), 7.52 (dd, J=8.6, 2.3 Hz, 1H), 5.27 (s, 1H), 4.77 (ddt, J=9.5, 6.4,3.5 Hz, 1H), 4.16 (t, J=9.0 Hz, 1H), 3.90 (dd, J=9.0, 6.1 Hz, 1H), 3.71(d, J=12.5 Hz, 1H), 3.59 (d, J=12.5 Hz, 1H), 3.28 (s, 3H).

Example 2 Synthesis of(5R)-3-[3,5-difluoro-4-(4-fluoro-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one

Step A: Synthesis of4-[2,6-difluoro-4-(2,2,5,5-tetramethyl-1,2,5-azadisilolidin-1-yl)phenyl]tetrahydro-2H-thiopyran-4-ol1,1-dioxide

Sec-Butyllithium (Sec-BuLi) (44.2 mL, 57.5 mmol) was added to a stirredsolution of1-(3,5-difluorophenyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine (12 g,44.2 mmol) in THF (120 mL) at −78° C. under nitrogen and the reactionmixture was allowed to stir for 2 h. Dihydro-2H-thiopyran-4(3H)-one1,1-dioxide (6.88 g, 46.4 mmol) was added, and the reaction mixture wasallowed to stir for 2 h. A saturated aqueous solution of ammoniumchloride (300 mL) was added to the reaction mixture, and the resultingmixture was extracted with ethyl acetate (3×100 mL). The combinedorganic layers were dried over sodium sulfate. The mixture was filteredand the filtrate was concentrated under reduced pressure to afford thetitle compound in sufficient purity for use in the next step.

Step B: Synthesis of4-(4-amino-2,6-difluorophenyl)tetrahydro-2H-thiopyran-4-ol 1,1-dioxide

Potassium carbonate (6.59 g, 47.7 mmol) was added to a solution of4-[2,6-difluoro-4-(2,2,5,5-tetramethyl-1,2,5-azadisilolidin-1-yl)phenyl]tetrahydro-2H-thiopyran-4-ol1,1-dioxide (10 g) in methanol (100 mL) at ambient temperature, and thereaction mixture was allowed to stir for 3 h. Water (30 mL) was thenadded to the reaction mixture, and the resulting mixture wasconcentrated, under reduced pressure, to remove any methanol. Theresulting mixture was filtered and the precipitate was washed withpetroleum ether/ethyl acetate (2/1). The resulting solid was dried underreduced pressure to afford the title compound. ¹H NMR (500 MHz,DMSO-d₆): δ 6.12 (d, J=13.5 Hz, 2H), 5.67 (s, 2H), 5.52 (br s, 1H), 3.37(br d, J=2.5 Hz, 2H), 2.96 (br d, J=11.5 Hz, 2H), 2.48-2.44 (m, 2H),2.28 (br d, J=13.0 Hz, 2H).

Step C: Synthesis of benzyl[3,5-difluoro-4-(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl]carbamate

N,N-dimethylaniline (6.29 g, 51.9 mmol) was added to a solution of4-(4-amino-2,6-difluorophenyl)tetrahydro-2H-thiopyran-4-ol 1,1-dioxide(7.2 g, 26.0 mmol) in THF (80 mL) at 0° C., and the reaction mixture wasallowed to stir for 20 min. Benzyl chloroformate (3.89 mL, 27.3 mmol)was added slowly, and the reaction mixture was allowed to slowly warm toambient temperature and was stirred for 4 h. Water (40 mL) was thenadded to the reaction mixture, and the resulting mixture was extractedwith ethyl acetate (3×30 mL). The organic layers were combined, driedover sodium sulfate. The resulting mixture was filtered, and thefiltrate concentrated under reduced pressure. The resulting residue waswashed with petroleum ether (4×20 mL). The resulting mixture wasfiltered, and the precipitate washed with ethyl acetate/petroleum ether(1/1; 2×10 mL). The resulting solid was dried under reduced pressure toafford the title compound in sufficient purity for use in the next step.MS (ESI) m/z: 394.1 [M−H₂O+H⁺]. ¹H NMR (DMSO-d₆, 400 MHz): δ 10.18 (s,1H), 7.45-7.33 (m, 5H), 7.10 (d, J=12.8 Hz, 2H), 5.79 (br s, 1H), 5.15(s, 2H), 3.39 (br s, 2H), 2.99 (br d, J=12.8 Hz, 2H), 2.59-2.51 (m, 2H),2.33-2.25 (m, 2H).

Step D: Synthesis of benzyl[3,5-difluoro-4-(4-fluoro-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl]carbamate

Bis(2-methoxyethyl)aminosulfur trifluoride (5.75 mL, 31.2 mmol) wasadded to a solution of benzyl[3,5-difluoro-4-(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl]carbamate(9.0 g, 20.8 mmol) in dichloromethane (60 mL) at 0° C., and the reactionmixture was allowed to warm to ambient temperature and stirred for 2 h.A saturated aqueous solution of sodium bicarbonate (40 mL) was added tothe reaction mixture, and the resulting mixture was concentrated underreduced pressure to remove dichloromethane. The resulting mixture wasfiltered, and the precipitate was washed with water (4×20 mL), petroleumether (3×30 mL), and ethyl acetate (10 mL) sequentially. The resultingsolid was dried under reduced pressure to afford the title compound. ¹HNMR (DMSO-d₆, 400 MHz): δ 10.32 (s, 1H), 7.46-7.33 (m, 5H), 7.20 (d,J=12.8 Hz, 2H), 5.18 (s, 2H), 3.45-3.36 (m, 2H), 3.18 (br d, J=12.8 Hz,2H), 2.80-2.60 (m, 4H).

Step E: Synthesis of(5R)-3-[3,5-difluoro-4-(4-fluoro-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one

Lithium tert-butoxide (4.36 g, 54.4 mmol) was added to a solution ofbenzyl[3,5-difluoro-4-(4-fluoro-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl]carbamate(7.5 g, 18.14 mmol) in THF (140 mL) at 0° C., and the reaction mixtureallowed to stir for 20 min. (R)-oxiran-2-ylmethyl butyrate (3.92 g, 27.2mmol) was then added, and the reaction mixture was warmed to ambienttemperature and allowed to stir for 16 h. The reaction mixture waspoured into a cold, saturated aqueous solution of ammonium chloride (400mL) and the resulting mixture was concentrated under reduced pressure toremove THF. The resulting mixture was filtered, and the precipitatecollected. The precipitate was purified by preparative HPLC, elutingwith a gradient of acetonitrile: water containing 10 mM ammoniumcarbonate—20:80 to 50:50 to afford the title compound. MS (ESI) m/z:380.0 [M+H⁺]. ¹H NMR (DMSO-d₆, 400 MHz): δ 7.39 (d, J=12.8 Hz, 2H), 5.23(t, J=5.6 Hz, 1H), 4.79-4.71 (m, 1H), 4.07 (t, J=9.2 Hz, 1H), 3.83 (dd,J=9.2, 6.0 Hz, 1H), 3.71-3.64 (m, 1H), 3.58-3.51 (m, 1H), 3.47-3.38 (m,2H), 3.19 (br d, J=12.0 Hz, 2H), 2.83-2.61 (m, 4H).

Example 3 Synthesis of{(5R)-3-[3,5-difluoro-4-(4-fluoro-1,1-dioxo-1λ⁶-thian-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyldihydrogen phosphate

To a solution of(R)-3-(3,5-difluoro-4-(4-fluoro-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one(500 mg, 1.32 mmol) in tetrahydrofuran (8 mL) at 0° C. was addedtriethylamine (0.551 mL, 3.95 mmol) followed by phosphorus(V)oxychloride (0.369 mL, 3.95 mmol) and the reaction mixture allowed tostir for 3 h. Water (20 mL) was added, and the resulting mixtureconcentrated under reduced pressure and the filtered. The precipitatewas purified by preparative HPLC, eluting with a gradient ofacetonitrile:water containing 0.05% HCl—15:85 to 35:65 to afford thetitle compound. MS (ESI) m/z: 460.2 [M+H⁺]. ¹H NMR (DMSO-d₆, 400 MHz): δ7.38 (d, J=12.8 Hz, 2H), 4.93 (br s, 1H), 4.15 (t, J=9.6 Hz, 1H),4.11-3.98 (m, 2H), 3.83 (dd, J=9.2, 6.0 Hz, 1H), 3.47-3.37 (m, 2H), 3.20(br d, J=13.6 Hz, 2H), 2.83-2.63 (m, 4H).

The following compounds were made using the methods described in Example1 or 2, substituting the appropriate reactants and/or reagents.

MS Example Structure IUPAC Name (M + H⁺) 4

(5R)-3-[2-fluoro-4′- (methylsulfanyl)[1,1′- biphenyl]-4-yl]-5-(hydroxymethyl)-1,3- oxazolidin-2-one 334.1 5

(5R)-3-[2-fluoro-3′- (methylsulfanyl)[1,1′- biphenyl]-4-yl]-5-(hydroxymethyl)-1,3- oxazolidin-2-one 334.1 6

(5R)-3-[3-fluoro-4- ([1,2,4]triazolo[1,5- a]pyridin-6-yl)phenyl]-5-(hydroxymethyl)-1,3- oxazolidin-2-one 329.1 7

2'-fluoro-4'-[(5R)-5- (hydroxymethyl)-2-oxo- 1,3-oxazolidin-3-yl][1,1′-biphenyl]-4-sulfonamide 367.1 8

(5R)-3-[3-fluoro-4- ([1,2,4]triazolo[1,5- a]pyridin-7-yl)phenyl]-5-(hydroxymethyl)-1,3- oxazolidin-2-one 329.1 9

(5R)-3-[3-fluoro-4- ([1,2,4]triazolo[4,3- a]pyridin-6-yl)phenyl]-5-(hydroxymethyl)-1,3- oxazolidin-2-one 329.1 10

2'-fluoro-4'-[(5R)-5- (hydroxymethyl)-2-oxo- 1,3-oxazolidin-3-yl][1,1′-biphenyl]-3-carboxamide 331.1 11

(5R)-3-(2-fluoro-4′- hydroxy[1,1'-biphenyl]-4- yl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one 304.1 12

(5R)-3-[2-fluoro-4'-(2- hydroxyethoxy)[1,1′- biphenyl]-4-yl]-5-(hydroxymethyl)-1,3- oxazolidin-2-one 348.0 13

2'-fluoro-4'-[(5R)-5- (hydroxymethyl)-2-oxo- 1,3-oxazolidin-3-yl][1,1′-biphenyl]-3-carbonitrile 313.1 14

(5R)-3-[4'-(1,3- dimethylazetidine-3- sulfonyl)-2-fluoro[1,1′-biphenyl]-4-yl]-5- (hydroxymethyl)- 1,3-oxazolidin-2-one 435.1 15

4-{2,6-difluoro-4-[(5R)- 5-(hydroxymethyl)- 2-oxo-1,3-oxazolidin-3-yl]phenyl}-3,6-dihydro- 1λ6-thiopyran- 1,1(2H)-dione 359.9 16

4-{2,6-difluoro-4-[(5R)-5- (hydroxymethyl)-2-oxo- 1,3-oxazolidin-3-yl]phenyl}-1,1-dioxo-1λ6- thiane-4-carbonitrile 387.1 17

5-{2,6-difluoro-4-[(5R)-5- (hydroxymethyl)-2-oxo- 1,3-oxazolidin-3-yl]phenyl}hexahydro-2λ6- thieno[3,4-c]pyrrole-2,2(1H)-dione 389.0 18

(5R)-3-[4-(5-acetyl-2,5- diazabicyclo[4.1.0]heptan-2-yl)-3,5-difluorophenyl]- 5-(hydroxymethyl)-1,3- oxazolidin-2-one 368.119

(5R)-3-[3-fluoro-4-(3- methyl[1,2,4]triazolo[4,3-a]pyridin-7-yl)phenyl]-5- (hydroxymethyl)-1,3- oxazolidin-2-one 343.0 20

(5R)-3-[2-fluoro-4′-(1- methylazetidine-3- sulfonyl)[1,1′-biphenyl]-4-yl]-5-(hydroxymethyl)- 1,3-oxazolidin-2-one 421.0 21

(5R)-3-{4-[5- (cyclopropanecarbonyl)- 2,5- diazabicyclo[4.1.0]heptan-2-yl]-3,5-difluorophenyl}- 5-(hydroxymethyl)-1,3- oxazolidin-2-one 394.122

4-{2,6-difluoro-4-[(5R)-5- (hydroxymethyl)-2-oxo- 1,3-oxazolidin-3-yl]phenyl}-1λ⁶- thiomorpholine-1,1-dione 363.0 23

(5R)-3-[4'-(1,3- dimethylazetidine-3- sulfonyl)[1,1'-biphenyl]-4-yl]-5-(hydroxymethyl)- 1,3-oxazolidin-2-one 417.2 24

4-fluoro-4-[2-fluoro-4- [(5R)-5-(hydroxymethyl)- 2-oxo-1,3-oxazolidin-3-yl]phenyl}-1λ⁶-thiane-1,1- dione 362.1 25

4-fluoro-4-{2,3,6-trifluoro- 4-[(5R)-5- (hydroxymethyl)-2-oxo-1,3-oxazolidin-3- yl]phenyl}-1λ⁶-thiane-1,1- dione 398.1 26

5-{2-fluoro-4-[(5R)-5- (hydroxymethyl)-2-oxo- 1,3-oxazolidin-3-yl]phenyl}-1- methylpyridin-2(1H)-one 319.0 27

4-{2,6-difluoro-4-[(5R)-5- (hydroxymethyl)-2-oxo- 1,3-oxazolidin-3-yl]phenyl}-1- (methylimino)-1λ⁶- thiomorpholin-1-one 376.0 28

(5R)-5-(hydroxymethyl)- 3-[4′- (methanesulfonyl)[1,1′-biphenyl]-4-yl]-1,3- oxazolidin-2-one 348.0 29

(5R)-3-[4′- (cyclobutanesulfonyl)-2- fluoro[1,1′-biphenyl]-4-yl]-5-(hydroxymethyl)- 1,3-oxazolidin-2-one 406.1 30

4-{2-chloro-6-fluoro-4- [(5R)-5-(hydroxymethyl)- 2-oxo-1,3-oxazolidin-3-yl]phenyl}-4-fluoro-1λ⁶- thiane-1,1-dione 396.0 31

4-{2-chloro-4-[(5R)-5- (hydroxymethyl)-2-oxo- 1,3-oxazolidin-3-yl]phenyl}-4-fluoro-1λ⁶- thiane-1,1-dione 378.0 32

(5R)-3-[4′- (cyclopropanesulfonyl)[1, 1′-biphenyl]-4-yl]-5-(hydroxymethyl)-1,3- oxazolidin-2-one 374.1 33

(5R)-5-(hydroxymethyl)- 3-[4′-(oxetane-3- sulfonyl)[1,1′-biphenyl]-4-yl]-1,3-oxazolidin-2-one 389.9 34

4-{2,6-difluoro-4-[(5R)-5- (hydroxymethyl)-2-oxo- 1,3-oxazolidin-3-yl]phenyl}-4-hydroxy- 1λ⁶-thiane-1,1-dione 360.0 35

4-fluoro-4-{4-[(5R)-5- (hydroxymethyl)-2-oxo- 1,3-oxazolidin-3-yl]-2-methylphenyl}-1λ⁶- thiane-1,1-dione 358.1 36

4-fluoro-4-{4-[(5R)-5- (hydroxymethyl)-2-oxo- 1,3-oxazolidin-3-yl]phenyl}-1λ⁶-thiane-1,1- dione 344.1 37

4-fluoro-4-{4-[(5R)-5- (hydroxymethyl)-2-oxo- 1,3-oxazolidin-3-yl]-2-(trifluoromethyl)phenyl}- 1λ⁶-thiane-1,1-dione 412.1 38

(5R)-3-[4′-(azetidine-1- sulfonyl)-2-fluoro[1,1′- biphenyl]-4-yl]-5-(hydroxymethyl)-1,3- oxazolidin-2-one 407.0 39

(5R)-3-{2-fluoro-4′- (methanesulfonyl)methyl] [1,1′-biphenyl]-4-yl}-5-(hydroxymethyl)-1,3- oxazolidin-2-one 380.1 40

4-{2,6-difluoro-4-[(5R)-5- (hydroxymethyl)-2-oxo- 1,3-oxazolidin-3-yl]phenyl}-1λ6-thiane- 1,1-dione 362.1 41

4-{2,6-difluoro-4-[(5R)-5- (hydroxymethyl)-2-oxo- 1,3-oxazolidin-3-yl]phenyl}-4-methyl-lλ⁶- thiane-1,1-dione 376.1

Biological Assays

Biological Assays

Mycobacterium tuberculosis (Mtb) Growth Assay

Inhibition of Mycobacterium tuberculosis (Mtb) growth was assessed ontwo in vivo-relevant carbon sources, glucose and cholesterol, at pH 6.8.For glucose as a carbon source, the media consisted of Middlebrook 7H9broth supplemented with 4 g/L glucose, 0.08 g/L NaCl, 5 g/L BSA fractionV and 0.05% tyloxapol. For cholesterol as a carbon source, the mediaconsisted of Middlebrook 7H9 broth supplemented with 97 mg/Lcholesterol, 0.08 g/L NaCl, 5 g/L BSA fraction V and 0.05% tyloxapol.Mtb expressing green fluorescent protein (Mtb-GFP; H37Rv pMSP12::GFP)was pre-adapted to growth on the relevant carbon source in Middlebrook7H9-broth base supplemented with bovine serum albumin and tyloxapolprior to the screen. Bacteria were dispensed into 384-well microtiterplates at approximately 2×10⁴ actively growing cells in 24 μL volumesper well. Microtiter plates were pre-dispensed with 0.2 μL compound,dimethylsulfoxide (negative control) or rifampicin (25 μM; positivecontrol). Cells were exposed to 2-fold serial dilutions of compoundsfrom 50 μM to 0.049 μM. In some experiments, compounds were tested atlower concentrations. Growth inhibition was assessed after a 7-daygrowth period by measuring fluorescence using a spectrophotometer. Innegative control wells, cells were still actively growing at the time ofreadout. The lowest concentration of test compound required to inhibit95% of the growth of the bacteria was defined as the MITC95. All studieswere done in a BSL3 facility. Mitochondrial protein synthesis assay

Inhibition of mitochondrial protein synthesis was assessed in HepG2cells by comparing the levels of two subunits of oxidativephosphorylation enzyme complexes, subunit I of Complex IV (COX-I) andthe 70 kDa subunit of Complex II (SDH-A). COX-I is mitochondrial DNAencoded and SDH-A is nuclear DNA encoded. HepG2 cells were seeded in96-well collagen coated plates at 8,000 cells per well and exposed to2-fold serial dilutions of compounds from 100 μM to 6.25 μM. Microtiterplates were incubated for approximately 5 replication cycles (4 days)prior to assessment of protein levels using a kit as described by themanufacturer (ab110217 MitoBiogenesis In Cell ELISA Kit, Abcam,Cambridge, Mass.). Inhibition of mitochondrial protein synthesis wasexpressed as a ratio of COX-1 to SDH-A levels and a ratio of COX-1 tototal viable cell amount (determined by Janus Green (JG) staining).

Mtb Cho Mtb Glu MPS Example MITC95_μM MITC95_μM IC50_μM 1 1.2 1.0 7 22.2 1.9 >100 4 0.24 0.21 >100 7 0.96 0.77 1.7 8 1.8 1.5 3.7 12 0.39 0.7819 14 0.78 0.78 23 15 1.6 1.6 >100 16 1.6 1.6 50 17 3.1 2.3 >100 18 3.13.1 >100 19 1.2 1.2 18 20 0.39 0.39 7.4 21 3.1 6.3 >13 22 6.3 3.9 >10023 3.1 1.6 >100 24 6.3 6.3 >50 25 6.3 6.3 >100 26 6.3 6.3 28 27 6.36.3 >100 28 1.6 1.6 32 29 3.1 3.1 >100 30 13 6.3 >100 31 13 13 >100 323.1 3.1 30 33 2.3 3.1 9.7 34 25 25 >100 35 50 25 >100 36 38 50 >50 37 5050 >100 38 6.3 6.3 >13 39 1.2 1.6 1.5 41 9.4 6.3 >100 linezolid 3.144.58 8

What is claimed:
 1. A compound of formula I

or a pharmaceutically acceptable salt thereof, wherein: E is a6-membered aryl or a 5- or 6-membered heteroaryl containing from one tothree heteroatoms independently selected from S, O, and N, wherein saidaryl and said heteroaryl are optionally substituted with up to foursubstituents, which are independently selected from halogen, —CN, —CF₃,—CHF₂, —CH₂NH₂, —CH₂NHCOCH₃, —OCF₃, —OCHF₂, —OH, —O—(C₁-C₆)alkyl, C₁-C₆alkyl, and C₃-C₆ cycloalkyl; A is a heterocycle optionally substitutedwith up to four R⁸, or an aryl optionally substituted with up to fourR⁸; each occurrence of R⁸ is independently selected from H, halogen,C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₃-C₆ heterocycloalkyl, —OC₁-C₆ alkyl,benzyl, —OCF₃, —OCHF₂, —OR³, ═O, —CN, —NO₂, —SR³, —SF₅, —SCF₃, —SOR³,—S₂R³, —S(═O)(═N(R², —N(R²)₂, —NR²COR³, —SO₂N(R²)₂, —NR²SO₂R³, —COOH,—COR⁹, —COOR³, —CON(R²)₂, —CO(R²)₂ and —C(R⁹)₂N(R²)₂, wherein said C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, —OC₁-C₆ alkyl, andbenzyl are optionally substituted with up to four F, —OCH₃, —OH, ═O,NH₂, NHCH₃, SO₂R³, and N(CH₃)₂; each occurrence of R² is independentlyselected from H, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₃-C₆ cycloalkyl,wherein said C₁-C₆alkyl, said C₂-C₆alkenyl, and said C₃-C₆cycloalkyl canbe optionally substituted with up to four substituents, which areindependently selected from halogen, —OCH₃, —OH, —NH₂, —NHCH₃, and—N(CH₃)₂; R³ is H, C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₆heterocycloalkyl andC₃-C₆cycloalkyl, wherein said C₁-C₆alkyl, said C₂-C₆alkenyl, saidC₃-C₆heterocycloalkyl and said C₃-C₆cycloalkyl can be optionallysubstituted with up to four substituents, which are independentlyselected from halogen, methyl, —OCH₃, —OH, —NH₂, —NHCH₃, and —N(CH₃)₂;and each occurrence of R⁹ is independently selected from H, C₁-C₆alkyl,and C₃-C₆cycloalkyl.
 2. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein A is:

wherein R⁸ represents one, two, three or four optional ring carbonsubstituents, which can be the same or different each occurrence of andwherein each occurrence of R⁸ is independently selected from H, halogen,C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, benzyl, —OCHF₂,—OR³, ═O, —CN, —NO₂, —SR³, —SF₅, —SCF₃, —SOR³, —SO₂R³, —S(═O)(═N(R²,—N(R²)₂, —NR²COR³, —SO₂N(R²)₂, —NR²SO₂R³, —COOH, —COR⁹, —COOR³,—CON(R²)₂, —CO(R²)₂ and —C(R⁹)₂N(R²)₂, wherein said C₁-C₆ alkyl,C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, and benzyl are optionallysubstituted with up to four F, —OCH₃, —OH, ═O, NH₂, NHCH₃, SO₂R³, andN(CH₃)₂; each occurrence of R² is independently selected from H,C₁-C₆alkyl, C₂-C₆alkenyl, and C₃-C₆ cycloalkyl, wherein said C₁-C₆alkyl,said C₂-C₆alkenyl, and said C₃-C₆cycloalkyl can be optionallysubstituted with up to four substituents, which are independentlyselected from halogen, —OCH₃, —OH, —NH₂, —NHCH₃, and —N(CH₃)₂; R³ is H,C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₆heterocycloalkyl and C₃-C₆cycloalkyl,wherein said C₁-C₆ alkyl, said C₂-C₆alkenyl, said C₃-C₆heterocycloalkyland said C₃-C₆cycloalkyl can be optionally substituted with up to foursubstituents, which are independently selected from halogen, methyl,—OCH₃, —OH, —NH₂, —NHCH₃, and —N(CH₃)₂; and each occurrence of R⁹ isindependently selected from H, C₁-C₆ alkyl, and C₃-C₆cycloalkyl.
 3. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein A is:

wherein: m= is 0, 1, 2, or 3; each occurrence of R⁸ is independentlyselected from H, halogen, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₃-C₆heterocycloalkyl, —OC₁-C₆alkyl, benzyl, —OCF₃, —OCHF₂, —OR³, ═O,—CN, —NO₂, —SR³, —SF₅, —SCF₃, —SOR³, —SO₂R³, —S(═O)(═N(R², —N(R²)₂,—NR²COR³, —SO₂N(R²)₂, —NR²SO₂R³, —COOH, —COR⁹, —COOR³, —CON(R²)₂,—CO(R²)₂ and —C(R⁹)₂N(R²)₂, wherein said C₁-C₆alkyl, C₃-C₆cycloalkyl,C₃-C₆heterocycloalkyl, —OC₁-C₆ alkyl, and benzyl are optionallysubstituted with up to four F, —OCH₃, —OH, ═0, NH₂, NHCH₃, SO₂R³, andN(CH₃)₂; each occurrence of R² is independently selected from H,C₁-C₆alkyl, C₂-C₆alkenyl, and C₃-C₆ cycloalkyl, wherein said C₁-C₆alkyl,said C₂-C₆alkenyl, and said C₃-C₆cycloalkyl can be optionallysubstituted with up to four substituents, which are independentlyselected from halogen, —OCH₃, —OH, —NH₂, —NHCH₃, and —N(CH₃)₂; R³ is H,C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₆heterocycloalkyl and C₃-C₆cycloalkyl,wherein said C₁-C₆alkyl, said C₂-C₆alkenyl, said C₃-C₆heterocycloalkyland said C₃-C₆cycloalkyl can be optionally substituted with up to foursubstituents, which are independently selected from halogen, methyl,—OCH₃, —OH, —NH₂, —NHCH₃, and —N(CH₃)₂; and each occurrence of R⁹ isindependently selected from H, C₁-C₆alkyl, and C₃-C₆cycloalkyl R¹⁰ isselected from H, C₁-C₆alkyl and C₃-C₆cycloalkyl, wherein said C₁-C₆alkyland said C₃-C₆ cycloalkyl are optionally substituted with from one tofour substituents, which are independently selected from F, —OCH₃, —OH,NH₂, NHCH₃, and N(CH₃)₂; R¹¹ is selected from H, C₁-C₆alkyl andC₃-C₆cycloalkyl, —COR⁹, —COOR³, —CON(R⁹)₂, and —SO₂R⁹; each occurrenceof R¹² is independently selected from H, halogen, C₁-C₆alkyl,C₃-C₆cycloalkyl, benzyl, —OCF₃, —OCHF₂, —OR³, —CN, —NO₂, —SR³, —SF₅,—SCF₃, —SOR³, —SO₂R³, —S(═O)(═N)R², —N(R²)₂, —NR²COR³, —SO₂N(R²)₂,—NR²SO₂R³, —COOH, —COR⁹, —COOR³, —CON(R²)₂, and —C(R⁹)₂N(R²)₂, whereinsaid C₁-C₆ alkyl, C₃-C₆cycloalkyl, and benzyl are optionally substitutedwith up to four F, —OCH₃, —OH, NH₂, NHCH₃, and N(CH₃)₂; R¹³ is selectedfrom H, halogen, C₁-C₆alkyl, C₃-C₆cycloalkyl, benzyl, —OCF₃, —OCHF₂,—OR³, —CN, —NO₂, —SR³, —SF₅, —SCF₃, —SOR³, —SO₂R³, —S(═O)(═N)R²,—N(R²)₂, —NR²COR³, —SO₂N(R²)₂, —NR²SO₂R³, —COOH, —COR⁹, —COOR³,—CON(R²)₂, and —C(R⁹)₂N(R²)₂, wherein said C₁-C₆ alkyl, C₃-C₆cycloalkyl,and benzyl are optionally substituted with up to four F, —OCH₃, —OH,NH₂, NHCH₃, and N(CH₃)₂; and W is selected from O, S, SO, SO₂, andS(═O)(═NH); and and wherein

represents a double or a single bond.
 4. The compound of claim 1, or apharmaceutically acceptable salt thereof, having the formula:

wherein A is a heterocycle optionally substituted with up to four R⁸, oran aryl optionally substituted with up to four R⁸; each occurrence of R⁸is independently selected from H, halogen, C₁-C₆ alkyl, C₃-C₆cycloalkyl,C₃-C₆ eterocycloalkyl, —OC₁-C₆alkyl, benzyl, —OCF₃, —OCHF₂, —OR³, ═O,—CN, —NO₂, —SR³, —SF₅, —SCF₃, —SOR³, —SO₂R³, —S(═O)(═N)R², —N(R²)₂,—NR²COR³, —SO₂N(R²)₂, —NR²SO₂R³, —COOH, —COR⁹, —COOR³, —CON(R²)₂,—CO(R²)₂ and —C(R⁹)₂N(R²)₂, wherein said C₁-C₆alkyl, C₃-C₆ cycloalkyl,C₃-C₆heterocycloalkyl, —OC₁-C₆ alkyl, and benzyl are optionallysubstituted with up to four F, —OCH₃, —OH, ═O, NH₂, NHCH₃, SO₂R³, andN(CH₃)₂; each occurrence of R² is independently selected from H,C₁-C₆alkyl, C₂-C₆alkenyl, and C₃-C₆ cycloalkyl, wherein said C₁-C₆alkyl,said C₂-C₆alkenyl, and said C₃-C₆cycloalkyl can be optionallysubstituted with up to four substituents, which are independentlyselected from halogen, —OCH₃, —OH, —NH₂, —NHCH₃, and —N(CH₃)₂; R³ is H,C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₆heterocycloalkyl and C₃-C₆cycloalkyl,wherein said C₁-C₆ alkyl, said C₂-C₆alkenyl, said C₃-C₆heterocycloalkyland said C₃-C₆cycloalkyl can be optionally substituted with up to foursubstituents, which are independently selected from halogen, methyl,—OCH₃, —OH, —NH₂, —NHCH₃, and —N(CH₃)₂; and each occurrence of R⁹ isindependently selected from H, C₁-C₆alkyl, and C₃-C₆ cycloalkyl.
 5. Thecompound of claim 4, or a pharmaceutically acceptable salt thereof,wherein A is:

wherein R⁸ represents one, two, three or four optional ring carbonsubstituents, which can be the same or different each occurrence of andwherein each occurrence of R⁸ is independently selected from H, halogen,C₁-C₆alkyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, —OC₁-C₆ alkyl,benzyl, —OCF₃, —OCHF₂, —OR³, ═O, —CN, —NO₂, —SR³, —SF₅, —SCF₃, —SOR³,—SO₂R³, —S(═O)(═N)R², —N(R²)₂, —NR²COR³, —SO₂N(R²)₂, —NR²SO₂R³, —COOH,—COR⁹, —COOR³, —CON(R²)₂, —CO(R²)₂ and —C(R⁹)₂N(R²)₂, wherein saidC₁-C₆alkyl, C₃-C₆cycloalkyl, C₃-C₆ heterocycloalkyl, —OC₁-C₆ alkyl, andbenzyl are optionally substituted with up to four F, —OCH₃, —OH, ═O,NH₂, NHCH₃, SO₂R³, and N(CH₃)₂; each occurrence of R² is independentlyselected from H, C₁-C₆alkyl, C₂-C₆alkenyl, and C₃-C₆ cycloalkyl, whereinsaid C₁-C₆alkyl, said C₂-C₆alkenyl, and said C₃-C₆cycloalkyl can beoptionally substituted with up to four substituents, which areindependently selected from halogen, —OCH₃, —OH, —NH₂, —NHCH₃, and—N(CH₃)₂; R³ is H, C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₆heterocycloalkyl andC₃-C₆cycloalkyl, wherein said C₁-C₆alkyl, said C₂-C₆alkenyl, saidC₃-C₆heterocycloalkyl and said C₃-C₆cycloalkyl can be optionallysubstituted with up to four substituents, which are independentlyselected from halogen, methyl, —OCH₃, —OH, —NH₂, —NHCH₃, and —N(CH₃)₂;and each occurrence of R⁹ is independently selected from H, C₁-C₆alkyl,and C₃-C₆cycloalkyl.
 6. The compound of claim 4, or a pharmaceuticallyacceptable salt thereof, wherein A is:

wherein R⁸ represents one, two, three or four optional ring carbonsubstituents, which can be the same or different each occurrence of andwherein each occurrence of R⁸ is independently selected from H, halogen,C₁-C₆alkyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, —OC₁-C₆ alkyl,benzyl, —OCF₃, —OCHF₂, —OR³, ═O, —CN, —NO₂, —SR³, —SF₅, —SCF₃, —SOR³,—SO₂R³, —S(═O)(═N)R², —N(R²)₂, —NR²COR³, —SO₂N(R²)₂, —NR²SO₂R³, —COOH,—COR⁹, —COOR³, —CON(R²)₂, —CO(R²)₂ and —C(R⁹)₂N(R²)₂, wherein saidC₁-C₆alkyl, C₃-C₆cycloalkyl, C₃-C₆ heterocycloalkyl, —OC₁-C₆ alkyl, andbenzyl are optionally substituted with up to four F, —OCH₃, —OH, ═O,NH₂, NHCH₃, SO₂R³, and N(CH₃)₂; each occurrence of R² is independentlyselected from H, C₁-C₆alkyl, C₂-C₆alkenyl, and C₃-C₆ cycloalkyl, whereinsaid C₁-C₆alkyl, said C₂-C₆alkenyl, and said C₃-C₆cycloalkyl can beoptionally substituted with up to four substituents, which areindependently selected from halogen, —OCH₃, —OH, —NH₂, —NHCH₃, and—N(CH₃)₂; R³ is H, C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₆heterocycloalkyl andC₃-C₆cycloalkyl, wherein said C₁-C₆ alkyl, said C₂-C₆alkenyl, saidC₃-C₆heterocycloalkyl and said C₃-C₆cycloalkyl can be optionallysubstituted with up to four substituents, which are independentlyselected from halogen, methyl, —OCH₃, —OH, —NH₂, —NHCH₃, and —N(CH₃)₂;and each occurrence of R⁹ is independently selected from H, C₁-C₆alkyl,and C₃-C₆cycloalkyl.
 7. The compound of claim 4, or a pharmaceuticallyacceptable salt thereof, wherein A is:

wherein R⁸ represents one, two, three or four optional ring carbonsubstituents, which can be the same or different each occurrence of andwherein each occurrence of R⁸ is independently selected from H, halogen,C₁-C₆alkyl, C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, —OC₁-C₆ alkyl,benzyl, —OCF₃, —OCHF₂, —OR³, ═O, —CN, —NO₂, —SR³, —SF₅, —SCF₃, —SOR³,—SO₂R³, —S(═O)(═N)R², —N(R²)₂, —NR²COR³, —SO₂N(R²)₂, —NR²SO₂R³, —COOH,—COR⁹, —COOR³, —CON(R²)₂, —CO(R²)₂ and —C(R⁹)₂N(R²)₂, wherein saidC₁-C₆alkyl, C₃-C₆cycloalkyl, C₃-C₆ heterocycloalkyl, —OC₁-C₆alkyl, andbenzyl are optionally substituted with up to four F, —OCH₃, —OH, ═O,NH₂, NHCH₃, SO₂R³, and N(CH₃)₂; each occurrence of R² is independentlyselected from H, C₁-C₆alkyl, C₂-C₆alkenyl, and C₃-C₆ cycloalkyl, whereinsaid C₁-C₆alkyl, said C₂-C₆alkenyl, and said C₃-C₆ cycloalkyl can beoptionally substituted with up to four substituents, which areindependently selected from halogen, —OCH₃, —OH, —NH₂, —NHCH₃, and—N(CH₃)₂; R³ is H, C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₆heterocycloalkyl andC₃-C₆cycloalkyl, wherein said C₁-C₆ alkyl, said C₂-C₆alkenyl, saidC₃-C₆heterocycloalkyl and said C₃-C₆cycloalkyl can be optionallysubstituted with up to four substituents, which are independentlyselected from halogen, methyl, —OCH₃, —OH, —NH₂, —NHCH₃, and —N(CH₃)₂;and each occurrence of R⁹ is independently selected from H, C₁-C₆alkyl,and C₃-C₆cycloalkyl.
 8. The compound of claim 4, or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is halogen or SO₂CH₃.
 9. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,having the structure:


10. The compound of claim 1, or a pharmaceutically acceptable saltthereof, having the structure:


11. The compound of claim 1, or a pharmaceutically acceptable saltthereof, having the structure:


12. The compound of claim 1, or a pharmaceutically acceptable saltthereof, having the structure:


13. A pharmaceutical composition which comprises a therapeuticallyeffective amount of a compound according to claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 14. A method for treating a bacterial infectionwhich comprises administering to a subject in need of such treatment (i)a therapeutically effective amount of a compound according to claim 1,or a pharmaceutically acceptable salt thereof.
 15. The method of claim10, wherein the bacterial infection is due to Mycobacteriumtuberculosis.
 16. (canceled)
 17. (canceled)
 18. The method according toclaim 15, further comprising the step of administering a secondtherapeutic agent for treating Mycobacterium tuberculosis.
 19. Themethod of claim 18, wherein the second therapeutic agent is selectedfrom the group consisting of: ethambutol, pyrazinamide, isoniazid,levofloxacin, moxifloxacin, gatifloxacin, ofloxacin, kanamycin,amikacin, capreomycin, streptomycin, ethionamide, prothionamide,cycloserine, terididone, para-aminosalicylic acid, clofazimine,clarithromycin, amoxicillin-clavulanate, thiacetazone,meropenem-clavulanate, and thioridazine.
 20. (canceled)
 21. A compoundof formula (II)

wherein: E is a 6-membered aryl or a 5- or 6-membered heteroarylcontaining from one to three heteroatoms independently selected from S,O, and N, wherein said aryl and said heteroaryl are optionallysubstituted with up to four substituents, which are independentlyselected from halogen, —CN, —CF₃, —CHF₂, —CH₂NH₂, —CH₂NHCOCH₃, —OCF₃,—OCHF₂, —OH, —O—(C₁-C₆)alkyl, C₁-C₆alkyl, and C₃-C₆cycloalkyl; A is aheterocycle optionally substituted with up to four R⁸, or an aryloptionally substituted with up to four R⁸; each occurrence of R⁸ isindependently selected from H, halogen, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₃-C₆heterocycloalkyl, —OC₁-C₆alkyl, benzyl, —OCF₃, —OCHF₂, —OR³, ═O,—CN, —NO₂, —SR³, —SF₅, —SCF₃, —SOR³, —SO₂R³, —S(═O)(═N)R², —N(R²)₂,—NR²COR³, —SO₂N(R²)₂, —NR²SO₂R³, —COOH, —COR⁹, —COOR³, —CON(R²)₂,—CO(R²)₂ and —C(R⁹)₂N(R²)₂, wherein said C₁-C₆alkyl, C₃-C₆cycloalkyl,C₃-C₆heterocycloalkyl, —OC₁-C₆alkyl, and benzyl are optionallysubstituted with up to four F, —OCH₃, —OH, ═O, NH₂, NHCH₃, SO₂R³, andN(CH₃)₂; each occurrence of R² is independently selected from H,C₁-C₆alkyl, C₂-C₆alkenyl, and C₃-C₆ cycloalkyl, wherein said C₁-C₆alkyl,said C₂-C₆alkenyl, and said C₃-C₆cycloalkyl can be optionallysubstituted with up to four substituents, which are independentlyselected from halogen, —OCH₃, —OH, —NH₂, —NHCH₃, and —N(CH₃)₂; R³ is H,C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₆heterocycloalkyl and C₃-C₆cycloalkyl,wherein said C₁-C₆alkyl, said C₂-C₆alkenyl, said C₃-C₆heterocycloalkyland said C₃-C₆cycloalkyl can be optionally substituted with up to foursubstituents, which are independently selected from halogen, methyl,—OCH₃, —OH, —NH₂, —NHCH₃, and —N(CH₃)₂; and each occurrence of R⁹ isindependently selected from H, C₁-C₆alkyl, and C₃-C₆ cycloalkyl.
 22. Thecompound of any of claim 21, or a pharmaceutically acceptable saltthereof, wherein A is:

wherein R⁸ represents up to four optional ring carbon substituents,which can be the same or different each occurrence of and wherein eachoccurrence of R⁸ is independently selected from H, halogen, C₁-C₆alkyl,C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, —OC₁-C₆alkyl, benzyl, —OCHF₂,—OR³, ═O, —CN, —NO₂, —SR³, —SF₅, —SCF₃, —SOR³, —SO₂R³, —S(═O)(═N(R²,—N(R²)₂, —NR²COR³, −SO₂N(R²)₂, —NR²SO₂R³, —COOH, —COR⁹, —COOR³,—CON(R²)₂, —CO(R²)₂ and —C(R⁹)₂N(R²)₂, wherein said C₁-C₆alkyl,C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, —OC₁-C₆alkyl, and benzyl areoptionally substituted with up to four F, —OCH₃, —OH, ═O, NH₂, NHCH₃,SO₂R³, and N(CH₃)₂; each occurrence of R² is independently selected fromH, C₁-C₆alkyl, C₂-C₆alkenyl, and C₃-C₆ cycloalkyl, wherein saidC₁-C₆alkyl, said C₂-C₆alkenyl, and said C₃-C₆cycloalkyl can beoptionally substituted with up to four substituents, which areindependently selected from halogen, —OCH₃, —OH, —NH₂, —NHCH₃, and—N(CH₃)₂; R³ is H, C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₆heterocycloalkyl andC₃-C₆cycloalkyl, wherein said C₁-C₆alkyl, said C₂-C₆alkenyl, saidC₃-C₆heterocycloalkyl and said C₃-C₆cycloalkyl can be optionallysubstituted with up to four substituents, which are independentlyselected from halogen, methyl, —OCH₃, —OH, —NH₂, —NHCH₃, and —N(CH₃)₂;and each occurrence of R⁹ is independently selected from H, C₁-C₆alkyl,and C₃-C₆cycloalkyl.
 23. The compound of any of claim 21, or apharmaceutically acceptable salt thereof, wherein A is:

wherein: m= is 0, 1, 2, or 3; each occurrence of R⁸ is independentlyselected from H, halogen, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₃-C₆heterocycloalkyl, —OC₁-C₆alkyl, benzyl, —OCF₃, —OCHF₂, —OR³, ═O,—CN, —NO₂, —SR³, —SF₅, —SCF₃, —SOR³, —SO₂R³, —S(═O)(═N)R², —N(R²)₂,—NR²COR³, —SO₂N(R²)₂, —NR²SO₂R³, —COOH, —COR⁹, —COOR³, —CON(R²)₂,—CO(R²)₂ and —C(R⁹)₂N(R²)₂, wherein said C₁-C₆alkyl, C₃-C₆cycloalkyl,C₃-C₆heterocycloalkyl, —OC₁-C₆alkyl, and benzyl are optionallysubstituted with up to four F, —OCH₃, —OH, ═O, NH₂, NHCH₃, SO₂R³, andN(CH₃)₂; R¹⁰ is selected from H, C₁-C₆alkyl and C₃-C₆cycloalkyl, whereinsaid C₁-C₆alkyl and said C₃-C₆ cycloalkyl are optionally substitutedwith from one to four substituents, which are independently selectedfrom F, —OCH₃, —OH, NH₂, NHCH₃, and N(CH₃)₂; R¹¹ is selected from H,C₁-C₆alkyl and C₃-C₆cycloalkyl, —COR⁹, —COOR³, —CON(R⁹)₂, and —SO₂R⁹;each occurrence of R¹² is independently selected from H, halogen,C₁-C₆alkyl, C₃-C₆cycloalkyl, benzyl, —OCF₃, —OCHF₂, —OR³, —CN, —NO₂,—SR³, —SF₅, —SCF₃, —SOR³, —SO₂R³, —S(═O)(═N)R², —N(R²)₂, —NR²COR³,—SO₂N(R²)₂, —NR²SO₂R³, —COOH, —COR⁹, —COOR³, —CON(R²)₂, and—C(R⁹)₂N(R²)₂, wherein said C₁-C₆alkyl, C₃-C₆cycloalkyl, and benzyl areoptionally substituted with up to four F, —OCH₃, —OH, NH₂, NHCH₃, andN(CH₃)₂; R¹³ is selected from H, halogen, C₁-C₆alkyl, C₃-C₆cycloalkyl,benzyl, —OCF₃, —OCHF₂, —OR³, —CN, —NO₂, —SR³, —SF₅, —SCF₃, —SOR³,—SO₂R³, —S(═O)(═N)R², —N(R²)₂, —NR²COR³, —SO₂N(R²)₂, —NR²SO₂R³, —COOH,—COR⁹, —COOR³, —CON(R²)₂, and —C(R⁹)₂N(R²)₂, wherein said C₁-C₆ alkyl,C₃-C₆cycloalkyl, and benzyl are optionally substituted with up to fourF, —OCH₃, —OH, NH₂, NHCH₃, and N(CH₃)₂; and W is selected from O, S, SO,SO₂, and S(═O)(═NH); and and wherein

represents a double or a single bond.
 24. The compound of claim 21, or apharmaceutically acceptable salt thereof, having the formula:

A is a heterocycle optionally substituted with up to four R⁸, or an aryloptionally substituted with up to four R⁸; each occurrence of R⁸ isindependently selected from H, halogen, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₃-C₆heterocycloalkyl, —OC₁-C₆alkyl, benzyl, —OCF₃, —OCHF₂, —OR³, ═O,—CN, —NO₂, —SR³, —SF₅, —SCF₃, —SOR³, —SO₂R³, —S(═O)(═N)R², —N(R²)₂,—NR²COR³, —SO₂N(R²)₂, —NR²SO₂R³, —COOH, —COR⁹, —COOR³, —CON(R²)₂,—CO(R²)₂ and —C(R⁹)₂N(R²)₂, wherein said C₁-C₆alkyl, C₃-C₆cycloalkyl,C₃-C₆heterocycloalkyl, —OC₁-C₆alkyl, and benzyl are optionallysubstituted with up to four F, —OCH₃, —OH, ═O, NH₂, NHCH₃, SO₂R³, andN(CH₃)₂; each occurrence of R² is independently selected from H,C₁-C₆alkyl, C₂-C₆alkenyl, and C₃-C₆ cycloalkyl, wherein said C₁-C₆alkyl,said C₂-C₆alkenyl, and said C₃-C₆cycloalkyl can be optionallysubstituted with up to four substituents, which are independentlyselected from halogen, —OCH₃, —OH, —NH₂, —NHCH₃, and —N(CH₃)₂; R³ is H,C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₆heterocycloalkyl and C₃-C₆cycloalkyl,wherein said C₁-C₆alkyl, said C₂-C₆alkenyl, said C₃-C₆heterocycloalkyland said C₃-C₆cycloalkyl can be optionally substituted with up to foursubstituents, which are independently selected from halogen, methyl,—OCH₃, —OH, —NH₂, —NHCH₃, and —N(CH₃)₂; and each occurrence of R⁹ isindependently selected from H, C₁-C₆alkyl, and C₃-C₆cycloalkyl.
 25. Thecompound of claim 24, or a pharmaceutically acceptable salt thereof,wherein A is:

wherein R⁸ represents up to four optional ring carbon substituents,which can be the same or different each occurrence of and wherein eachoccurrence of R⁸ is independently selected from H, halogen, C₁-C₆alkyl,C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, —OC₁-C₆alkyl, benzyl, —OCF₃,—OCHF₂, —OR³, ═O, —CN, —NO₂, —SR³, —SF₅, —SCF₃, —SOR³, —SO₂R³,—S(═O)(═N(R², —N(R²)₂, —NR²COR³, —SO₂N(R²)₂, —NR²SO₂R³, —COOH, —COR⁹,—COOR³, —CON(R²)₂, —CO(R²)₂ and —C(R⁹)₂N(R²)₂, wherein said C₁-C₆alkyl,C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, —OC₁-C₆alkyl, and benzyl areoptionally substituted with up to four F, —OCH₃, —OH, ═O, NH₂, NHCH₃,SO₂R³, and N(CH₃)₂; each occurrence of R² is independently selected fromH, C₁-C₆alkyl, C₂-C₆alkenyl, and C₃-C₆ cycloalkyl, wherein saidC₁-C₆alkyl, said C₂-C₆alkenyl, and said C₃-C₆cycloalkyl can beoptionally substituted with up to four substituents, which areindependently selected from halogen, —OCH₃, —OH, —NH₂, —NHCH₃, SO₂R³ and—N(CH₃)₂; R³ is H, C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₆heterocycloalkyl andC₃-C₆cycloalkyl, wherein said C₁-C₆alkyl, said C₂-C₆alkenyl, saidC₃-C₆heterocycloalkyl and said C₃-C₆cycloalkyl can be optionallysubstituted with up to four substituents, which are independentlyselected from halogen, methyl, —OCH₃, —OH, —NH₂, —NHCH₃, and —N(CH₃)₂.26. The compound of claim 24, or a pharmaceutically acceptable saltthereof, wherein A is:

wherein R⁸ represents up to four optional ring carbon substituents,which can be the same or different each occurrence of and wherein eachoccurrence of R⁸ is independently selected from H, halogen, C₁-C₆alkyl,C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, —OC₁-C₆alkyl, benzyl, —OCF₃,—OCHF₂, —OR³, ═O, —CN, —NO₂, —SR³, —SF₅, —SCF₃, —SOR³, —SO₂R³,—S(═O)(═N)R², —N(R²)₂, —NR²COR³, —SO₂N(R²)₂, —NR²SO₂R³, —COOH, —COR⁹,—COOR³, —CON(R²)₂, —CO(R²)₂ and —C(R⁹)₂N(R²)₂, wherein said C₁-C₆alkyl,C₃-C₆cycloalkyl, C₃-C₆ heterocycloalkyl, —OC₁-C₆alkyl, and benzyl areoptionally substituted with up to four F, —OCH₃, —OH, ═O, NH₂, NHCH₃,SO₂R³, and N(CH₃)₂; each occurrence of R² is independently selected fromH, C₁-C₆alkyl, C₂-C₆alkenyl, and C₃-C₆ cycloalkyl, wherein saidC₁-C₆alkyl, said C₂-C₆alkenyl, and said C₃-C₆cycloalkyl can beoptionally substituted with up to four substituents, which areindependently selected from halogen, —OCH₃, —OH, —NH₂, —NHCH₃, and—N(CH₃)₂; R³ is H, C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₆heterocycloalkyl andC₃-C₆cycloalkyl, wherein said C₁-C₆alkyl, said C₂-C₆alkenyl, saidC₃-C₆heterocycloalkyl and said C₃-C₆cycloalkyl can be optionallysubstituted with up to four substituents, which are independentlyselected from halogen, methyl, —OCH₃, —OH, —NH₂, —NHCH₃, and —N(CH₃)₂;and each occurrence of R⁹ is independently selected from H, C₁-Calkyl,and C₃-C₆ cycloalkyl.
 27. The compound of claim 24, or apharmaceutically acceptable salt thereof, wherein A is:

wherein R⁸ represents up to four optional ring carbon substituents,which can be the same or different each occurrence of and wherein eachoccurrence of R⁸ is independently selected from H, halogen, C₁-C₆alkyl,C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, —OC₁-C₆alkyl, benzyl, —OCHF₂,—OR³, ═O, —CN, —NO₂, —SR³, —SF₅, —SCF₃, —SOR³, —SO₂R³, —S(═O)(═N(R²,—N(R²)₂, —NR²COR³, —SO₂N(R²)₂, —NR²SO₂R³, —COOH, —COR⁹, —COOR³,—CON(R²)₂, —CO(R²)₂ and —C(R⁹)₂N(R²)₂, wherein said C₁-C₆alkyl,C₃-C₆cycloalkyl, C₃-C₆heterocycloalkyl, —OC₁-C₆alkyl, and benzyl areoptionally substituted with up to four F, —OCH₃, —OH, ═O, NH₂, NHCH₃,SO₂R³, and N(CH₃)₂; each occurrence of R² is independently selected fromH, C₁-C₆alkyl, C₂-C₆alkenyl, and C₃-C₆ cycloalkyl, wherein saidC₁-C₆alkyl, said C₂-C₆alkenyl, and said C₃-C₆cycloalkyl can beoptionally substituted with up to four substituents, which areindependently selected from halogen, —OCH₃, —OH, —NH₂, —NHCH₃, and—N(CH₃)₂; R³ is H, C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₆heterocycloalkyl andC₃-C₆cycloalkyl, wherein said C₁-C₆alkyl, said C₂-C₆alkenyl, saidC₃-C₆heterocycloalkyl and said C₃-C₆cycloalkyl can be optionallysubstituted with up to four substituents, which are independentlyselected from halogen, methyl, —OCH₃, —OH, —NH₂, —NHCH₃, and —N(CH₃)₂;and each occurrence of R⁹ is independently selected from H, C₁-C₆alkyl,and C₃-C₆cycloalkyl.
 28. The compound of claim 24, or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is halogen or SO₂CH₃.
 29. Thecompound of claim 21, or a pharmaceutically acceptable salt thereof,having the structure:


30. A pharmaceutical composition which comprises a therapeuticallyeffective amount of a compound according to claim 21, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 31. A method for treating a bacterial infectionwhich comprises administering to a subject in need of such treatment (i)a therapeutically effective amount of a compound according to claim 21,or a pharmaceutically acceptable salt thereof.
 32. The method of claim31, wherein the bacterial infection is due to Mycobacteriumtuberculosis.
 33. (canceled)
 34. (canceled)
 35. (canceled) 36.(canceled)
 37. (canceled)